Next Article in Journal
Effect of Nano-Sized Poly(Butyl Acrylate) Layer Grafted from Graphene Oxide Sheets on the Compatibility and Beta-Phase Development of Poly(Vinylidene Fluoride) and Their Vibration Sensing Performance
Previous Article in Journal
4-Pyridone-3-carboxamide-1-β-D-ribonucleoside (4PYR)—A Novel Oncometabolite Modulating Cancer-Endothelial Interactions in Breast Cancer Metastasis
Previous Article in Special Issue
Carotenoids from Marine Sources as a New Approach in Neuroplasticity Enhancement
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 23
Issue 10
10.3390/ijms23105772
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Venom Peptide Toxins Targeting the Outer Pore Region of Transient Receptor Potential Vanilloid 1 in Pain: Implications for Analgesic Drug Development

by
Sung-Min Hwang
1,†,
Youn-Yi Jo
2,†,
Cinder Faith Cohen
3,
Yong-Ho Kim
1,
Temugin Berta
3,* and
Chul-Kyu Park
1,*
1
Gachon Pain Center and Department of Physiology, Gachon University College of Medicine, Incheon 21999, Korea
2
Gil Medical Center, Department of Anesthesiology and Pain Medicine, Gachon University, Incheon 21565, Korea
3
Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, OH 45242, USA
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2022, 23(10), 5772; https://doi.org/10.3390/ijms23105772
Submission received: 10 March 2022 / Revised: 2 May 2022 / Accepted: 19 May 2022 / Published: 21 May 2022
(This article belongs to the Special Issue Role of Natural Compounds in Neurological Diseases)
Browse Figure
Versions Notes

Abstract

:
The transient receptor potential vanilloid 1 (TRPV1) ion channel plays an important role in the peripheral nociceptive pathway. TRPV1 is a polymodal receptor that can be activated by multiple types of ligands and painful stimuli, such as noxious heat and protons, and contributes to various acute and chronic pain conditions. Therefore, TRPV1 is emerging as a novel therapeutic target for the treatment of various pain conditions. Notably, various peptides isolated from venomous animals potently and selectively control the activation and inhibition of TRPV1 by binding to its outer pore region. This review will focus on the mechanisms by which venom-derived peptides interact with this portion of TRPV1 to control receptor functions and how these mechanisms can drive the development of new types of analgesics.

1. Introduction

The transient receptor potential vanilloid 1 (TRPV1) channel is a ligand-gated and non-selective cation channel that mediates physiological and pathophysiological functions in the peripheral nervous system [1,2]. TRPV1 is expressed in peripheral sensory neurons along with important signaling complexes that are associated with nociceptive mechanisms underlying various pain symptoms [3,4]. TRPV1 is activated by various noxious stimuli, such as heat, protons, plant and animal toxins, and bioactive lipids [1,5,6,7,8,9]. The different TRPV1 activation profiles elicited by different stimuli have been suggested to cause diverse pain sensations [7]. For example, endovanilloids are associated with inflammatory pain and hypersensitivity, while the exovanilloid toxin capsaicin causes acute pain [9]. For this reason, the TRPV1 receptor is a promising target in the search for novel analgesic drugs and therapeutic interventions for various pain conditions [10]. TRPV1 functions as a multimodal sensor for pain production [11], and the response elicited by TRPV1 antagonists depends on different conditions that affect the activity and inhibition of this channel [3].
Venoms from animals such as snakes, scorpions, marine cone snails, jellyfish, insects, and spiders are diverse and complex compounds that contain small molecules, peptides, and proteins [12,13]. This complex mixture can act on receptors or channels, causing irritation, paralysis, or pain [14,15]. While crude venom causes painful sensations through various mechanisms, some isolated toxins can promote analgesia by reducing nociceptive transmission [16,17,18,19]. Although the mechanism by which these toxins modulate pain remains elusive, multiple peptide toxins have been shown to act as ligands for various receptors and ion channels in the nervous system [13,20]. These peptides are stabilized by the formation of multiple disulfide bridges, which induce compact folding and are small in size, resulting in high thermal and chemical stability [21,22]. Therefore, these isolated peptides have become useful and potent pharmacological tools for investigating the structure and function of specific ion channels [13,23,24]. Recently, several venom-derived peptides have been reported to function as agonists or antagonists that bind to specific TRPV1 sites [6,25]. Therefore, these peptides can be considered important templates for the study of the structure and function of TRPV1 activity and the discovery of new analgesics.
Here, we present a brief summary of the venom-mediated modulation of TRPV1 function, focusing on peptides that specifically interact with the outer pore domain of TRPV1, with the purpose of elucidating TRPV1-mediated pain mechanisms.

2. General Characteristics of TRPV1

2.1. The TRP Superfamily and TRPV Family

Mammalian TRP channels comprise 28 members and are divided into six subfamilies based on sequence homology: canonical (TRPC), vanilloid (TRPV), ankyrin (TRPA), melastatin (TRPM), polycystin (TRPP), and mucolipin (TRPML) [1,2,3]. Most TRP channels belong to a large family group of non-selective and polymodal ion channels with diverse physiological functions and regulatory mechanisms and are implicated in different channelopathies [26,27,28]. TRPs are tetrameric channels formed by monomers with six transmembrane domains (S1–6) and cation-selective pores [26,29,30].
The TRPV family has a structure similar to that of other TRP channels, but with an additional three to five ankyrin repeat domains at the N-terminal end [31]. In addition, the TRPV family consists of six vanilloid members (TRPV1–6) with different functional features [29,32]. The TRPV1–4 channels form both homo- and heterodimers with mild Ca2+ selectivity, while TRPV5 and 6 are highly selective for Ca2+ [29,33,34]. Among the TRPV homologs, the TRPV1 channel has been particularly studied with regard to its role in nociception, and, as such, is the treatment target for various pain sensations [27,29,32]. Therefore, various compounds have been developed to downregulate or inactivate the activity of TRPV1 [29,33,34,35].

2.2. The Structure of TRPV1 Channel

TRPV1 is a homotetramer, where each homomeric subunit consists of six intracellular transmembrane core regions (S1–6) with a hydrophobic stretch (pore domain) between S5 and S6 (Figure 1) [36]. S1–4 are considered to contain a voltage sensor, an N-terminal ankyrin repeat, a linker, a pre-S1 linker, and a binding site for various agonists [1]. TRPV1 is structurally similar to the voltage-gated potassium (Kv) channel with a linker region between S4 and S5 that plays an important role in the allosteric coupling between channel domains and converts the conformational changes of S1–4 into pore gating [37]. This pore-forming loop of TRPV1 contains an outer pore region, a “turret” for channel activation, and is ion-selective [1,36]. The long N-terminus contains six ankyrin repeat domains that provide several binding sites, which are necessary for the recognition of several signaling molecules, such as calmodulin, adenosine triphosphate, phosphate groups, PI(4,5)P2, and calmodulin for modulating TRPV1 activation [38]. The C-terminus also interacts with various proteins and ligands [1]. In particular, TRPV1 has an amphipathic helix called the TRP box near the C-terminus, which connects the S6 helix with the C-terminus domain and is required for the allosteric channel activation [39,40].

2.3. The Function of the TRPV1 Channel

Due to its expression in the peripheral and central nervous systems, the TRPV1 channel has received attention for its involvement in mediating pain signals in physiological or pathological conditions [41]. TRPV1 is also involved in many other signals unrelated to nociception [42]. In the brain, TRPV1 can modulate the regulation of synaptic transmission, plasticity, development, and microglia-to-neuron communication [43]. Thus, TRPV1 channels are critical potential detectors of harmful stimuli as well as pain biomarkers in the brain [44]. In addition, the widespread expression of TRPV1 in peripheral tissues, including epithelial cells, the gastrointestinal tract, and immune cells, has been reported to be involved in multiple important functions in non-pain-related signal transmission [45]. Antagonists of TRPV1 inhibit pain behaviors in rodent models of cancer, osteoarthritis, and inflammation [46].

2.4. The Mechanism of Heat-Dependent Opening of TRPV1

TRPV1 is responsible for sensing body temperature, eliciting an increase in body temperature (hyperthermia) [47]. The knock out of TRPV1 in mice or TRPV1 antagonists induces prolonged hyperthermia, an undesired side effect, upon exposure to warm ambient temperature, whereas this effect is not seen in wild-type mice [48]. In addition, patients have shown long-lasting increases in body temperature after the administration of a TRPV1 antagonist [48,49]. Conversely, agonists of TRPV1, such as capsaicin, induce pain and a drop in body temperature (hypothermia) [50]. Although the TRPV1 channel is known as a high-temperature sensor that is activated above 43 °C, many of the mechanisms driving thermal sensation remain unknown [1,2]. Thermal-sensing regions of TRPV1 have been proposed to include the outer pore, cytosol, and proximal regions of the membrane [3]. Whether these regions directly detect heat or indirectly detect heat by participating in gating events downstream of thermal sensation remains debatable [4]. Additionally, it is unclear how these spatially separated regions are structured for heat-dependent gate opening and if they undergo sequential conformational rearrangements or changes in temperature activation [4,5]. Recent studies of the TRPV1 structure have revealed that the heat-induced transition of TRPV1 switches from a closed to open configuration at different temperatures [6,51]. Molecular dynamics simulations have revealed the TRPV1 structure in the closed and open states at 30 °C and 60 °C [6]. In the closed state, there is a constricted stably closed channel in the lower gate (near residue I679), whereas the upper gate (near residues G643 and M644) is dynamic and undergoes opening and (or) closing.
Open-state simulations at 60 °C have shown higher conformational changes upon thermal activation, and both the lower and upper gates are dynamic, with transient opening and (or) closing [7]. Therefore, G643 is more flexible than I679 and the upper gate can be opened more readily than the lower gate during gating transition [8]. In particular, the C-terminal domain, intracellular linker, and outer domains play a role in ligand and thermal sensation [2]. The pore helices S5 and S6 form a gate that regulates ion passage in the hydrated central cavity between the intracellular and extracellular gates [2]. Asparagine (N676) in the middle of the S6 helix adopts two conformational changes in the open and closed states [52]. In the closed state, peripheral cavities host several water molecules and the pore is partially dehydrated; N676 projects the side chain toward either the pore or four peripheral cavities located between the S6 helix and the S4–5 linker [53]. The application of activating stimulus dehydrates the peripheral cavities, causing N676 to rotate, altering the hydrophobic character of the molecular surface lining the pore, which promotes hydration and ion permeation, key components of TRPV1 activation [53].

2.5. The TRPV1 Pore

The TRPV1 structure includes a dual-gate channel pore with two constrictions (the upper and lower gates) located near the outer pore (residues G643 and M644) [6,25,54]. The two gates form a funnel-like shape, which spans from the extracellular face of the channel to the center of the membrane, creating a cation selectivity filter [55,56]. The lower gate is located in the middle of the S6 helix (residue I679) which lines the pore [55,57]. Channel opening occurs through a large structural rearrangement of the outer pore domain, including the pore helix and selectivity filter, accompanied by an expansion of the hydrophobic constriction of the lower gate, suggesting that this dual gating system undergoes dynamic fluctuations [2,55].

3. Functional Regulation of TRPV1 by Venom Peptide

3.1. Venom Peptides

3.1.1. Relevance to Pain and Analgesia

Natural venom toxins are complex mixtures of substances such as salts, small molecules, peptides, and proteins [58]. In particular, several painful venom components are neurotoxins that act directly or indirectly on specific ion channels in the peripheral sensory nervous system, thereby affecting pain sensation [12,20,59]. A wide range of peptide toxins show functional diversity in targeting ion channels and receptors involved in pain signaling pathways [23]. Furthermore, these peptides have a high potency, selectivity, and biological stability for the development of pharmacological probes and analgesics [60].

3.1.2. The Inhibitor Cystine Knot Domain of Venom Peptides

Peptides and proteins found in venomous animals contain high levels of tertiary structures stabilized by disulfide bonds [20,61]. Peptides containing the inhibitor cystine knot (ICK) motif are usually 26–50 amino acids in length and exhibit various activities, including ion channel blocking [62,63]. The ubiquitous ICK motif, which is the most well-known disulfide-rich framework, is defined as an antiparallel β-sheet stabilized by a cystine knot [64,65]. The main advantages of the use of ICK peptides for drug development are their resistance to proteases, high temperature, and harsh chemicals, which are attributed to their knotted structure [66]. Recent compounds reportedly developed from venoms have included peptide toxins that contain a specific structural motif with an ICK domain [67].

3.2. TRPV1 Activation by Venom Peptides

3.2.1. DkTx

The DkTx toxin, derived from the venom of the Malaysian earthtiger tarantula, binds to the extracellular pore domain of TRPV1, locking the receptor open and causing pain [68] (Table 1). DkTx consists of two ICK domains, known as K1 and K2 [69]. Each ICK domain contains six cysteine residues that form sulfide bridges (knot-like structures) [6]. DkTx can form a stable, non-covalent complex with the outer pore region of TRPV1 through the interaction between four of its residues and the S5 and S6 pore helix loops (I599 and F649, respectively) and S6 (A657 and F659, respectively) [6,70]. Furthermore, ICK peptide toxins can specifically interact with voltage-gated ion channels [71]. Thus, DkTx activates TRPV1, which belongs to the voltage-gated ion-channel superfamily [72].

3.2.2. Vanillotoxins (VaTx1–3)

VaTxs are ICK motif-containing peptides isolated from the venom of the tarantula Psalmopoeus cambridgei [6]. VaTxs act as TRPV1 agonists, activating pain sensation by binding to the extracellular pore domain of the channel, opening the pore, and triggering the influx of cations [6,54]. VaTx1 and VaTx2 also act as antagonists of the Kv2-type voltage-gated K+ channel (Kv2), causing paralysis and hyperexcitability [6]. Despite the similar structures of TRPV1 and Kv2, VaTx1–2 binds to the voltage-sensing domain of Kv2 rather than the pore domain [14].

3.2.3. RhTx

RhTx is a peptide toxin (27 amino acids) found in Scolopendra subspinipes mutilans (also known as the Chinese red-headed centipede) venom [79]. RhTx has two pairs of disulfide bonds: the N-terminus of the peptide contains no charged amino acids, whereas the C-terminus of the peptide is rich in charged amino acids [79,80]. Four charged residues (D20, K21, Q22, and E27) and one polar residue (R15) participate in RhTx-TRPV1 binding [89]. RhTx has a high-temperature dependence because an increase in temperature potentiates its activity; thus, RhTx is a potent TRPV1 activator at physiological body temperature, causing intense burning pain [6,80]. Specifically, RhTx binds to the outer pore region of TRPV1 as a selective TRPV1 activator and does not affect other TRPV channels (TRPV2–4) [6].

3.2.4. BmP01

BmP01 is a short peptide (29 amino acids) isolated from the venom of the scorpion Mesobuthus martensii with a typical ICK motif structure [5]. This toxin has dual functions, as it both activates TRPV1 and inhibits the Kv channel, thus resulting in a hyperexcitable nociceptive condition [82]. BmP01 binds to the outer pore domain of TRPV1, which contains three polar residues located in the pore helix-S6 loop (E649, T651, and E652 of hTRPV1) that are known to affect TRPV1 gating [5,81]. Bmp01 induces pain signals in wild-type but not in TRPV1 KO mice, suggesting that this peptide toxin could produce pain through TRPV1 activation [82].

3.3. TRPV1 Inhibition by Venom Peptides

3.3.1. Analgesic Polypeptide Heteractis crispa Toxin

Analgesic polypeptide Heteractis crispa (APHC)1–3 are 56-amino acid peptides derived from the sea anemone Heteractis crispa that bind to the outer loop of TRPV1 and induce analgesic activity during pain-related behavioral tests in rodents without causing hyperthermia [83,84,85]. Notably, APHCs enhance the TRPV1 response at low concentrations of capsaicin but block the response at high concentrations [83]. In addition, APHCs bind to the outer loop domain involved in proton activation [83]. This can directly affect the opening of the upper gate of TRPV1 because the binding site affects proton-binding conditions and can be allosterically coupled with APHC- or capsaicin-binding sites [83].

3.3.2. Heteractis crispa RG 21

Heteractis crispa RG 21 (HCRG21) is a new Kunitz-type peptide that shares a high structural homology with the Kunitz peptide (APHC)1–3 [6]. This peptide inhibits the capsaicin-induced ion current through TRPV1 [87] and results in a dramatic decrease in TRPV1-mediated tumor necrosis factor-α production in a model of carrageenan-induced pain [88]. Therefore, this new peptide has a pharmacological target as a TRPV1 antagonist. Altogether, the outer loop of TRPV1 is a crucial site to study, as various ligands that can bind to this site produce differential effects that have implications for the development of alternative pain therapeutics.

3.4. Complex between TRPV1 and Peptides (Toxins)

Peptide toxins can modulate TRPV1 activation by binding to specific domains, including the outer pore domain [6]. Various peptide toxins directly inhibit or activate this channel by binding to sites in the outer pore domain involved in the channel’s gating mechanism [90,91]. In particular, some toxins, including DxTx, BmP01, and RhTx, have been shown to activate or inhibit TRPV1 by binding to the outer pore domain of the channels (Figure 1) [6,90,91]. This implies that the outer pore region of TRPV1 is a common domain for binding and channel gating by different peptide animal toxins and highlights the importance of the outer pore domain in TRPV1 activation [36]. The outer pore region plays a role in TRPV1 activation because this raises the potential to allosterically modulate TRPV1 activation by other stimuli, including heat and proteins [36,92,93].

3.4.1. Open and Closed State: Dual Gating Mechanism

The TRPV1 structure showcases three distinct structural states: the closed state (apo condition) is the ligand-free condition; the partially open state is the capsaicin-binding condition; and the fully open state is the binding state caused by resiniferatoxin (RTX) and double-knot toxin (DkTx), both of which act as irreversible TRPV1 channel openers [36,94]. The closed state constricts the selectivity filter and lower gate [55,95]. The two open states of TRPV1 are determined by the binding state of capsaicin or RTX/DkTx [2,5]. When capsaicin binds, there is no change in the selectivity filter, whereas the lower gate expands significantly [36,96]. In contrast, when RTX/DkTx binds, the channel is fully open to the ion conduction pathway, where all constrictions are eliminated [6,25,36,83].

3.4.2. The Outer Pore Region of TRPV1

Two major TRPV1-binding sites are responsible for the open gating mechanism in response to multiple agonists and antagonists [1]. The first is a capsaicin binding site located in S3–4, and the second is an outer pore region that contains binding sites for various ligands, and, as such, is responsive to heat, protons, and venom peptide toxins [1,7,38,40,54,57,97,98]. Residues in this region are essential for the heat-mediated activation of TRPV1 [92]. Extracellular protons potentiate and activate TRPV1 through glutamate residues found in this region (E600 and E648) [99]. Furthermore, capsaicin binding induces the outward movement of the S4–5 linker, but few conformational changes occur in the outer pore region [100]. In contrast, large conformational changes occur during heat activation [94,101]. Some venom peptide toxins can allosterically modulate TRPV1 activation through the outer pore region domain [6]. RhTx activates TRPV1 through an allosteric mechanism and promotes TRPV1 opening by preferentially binding to the activated state [102]. RhTx also promotes heat activation by lowering the activation threshold temperature [102].

3.4.3. The Allosteric Coupling of TRPV1: Upper and Lower Gates

As the TRPV1 channel is key in the pain pathway, blocking TRPV1 activation could constitute a novel strategy to alleviate various pain sensations [95]. Allosteric conformational changes of TRPV1 are an interesting mechanism, as various vanilloid and venom peptide toxins interact with specific binding domains to affect the upper and lower gates of the open state of TRPV1 [103]. In the absence of an activating stimulus, both gates of TRPV1 remain closed, whereas the binding of an activating ligand causes both gates to partially or sequentially open [83]. For example, vanilloid agonists (vanillyl group) and capsaicin interact with the S4–5 linker of TRPV1 to induce conformational rearrangements (outward movement of the S4–5 linker) that are concomitant with the opening of the lower gate and result in small conformational changes in the outer pore region [73]. RhTx directly interacts with the outer pore helix and turret of TRPV1, which produces excruciating pain [79]. DkTx also binds to the outer binding domain of TRPV1, stabilizing the open state and evoking irreversible channel activation [54]. Notably, capsaicin and DkTx initiate different gating mechanisms through different binding domains within the TRPV1 pore turret domain [54]. Therefore, a difference in the movement of the outer pore region may be exploited to develop a modality-specific inhibitor of TRPV1 without eliciting adverse effects on body temperature and thermal sensation.

3.4.4. The Two Distinct Binding Sites of TRPV1

TRPV1 is a non-selective cation channel that is activated by various specific endogenous and exogenous ligands [56]. TRPV1 activation leads to painful burning sensations [1,55,104]. Exogenous agonists include dietary compounds (capsaicin and eugenol), non-dietary plant compounds (RTX), animal venoms, and other factors (noxious heat and extracellular pH) [38,105]. Endogenous agonists include bioactive lipids, inflammatory soups (bradykinin and histamine), and mediators of inflammation (LOX, a product of the lipoxygenases) [1,4,38,95]. These activators bind to the binding sites of the extracellular and intracellular domains of TRPV1, producing distinct pain sensations [2,36,95,97].
Notably, these binding sites are located in separate regions within the TRPV1 channel subunits and lead to various pain sensations [2,9]. For example, DkTx interacts with the outer pore domain and produces persistent pain through prolonged TRPV1 activation, whereas capsaicin, a key exogenous ligand for TRPV1, evokes a sensation of heat and acute pain [70,106]. Capsaicin can permeate the plasma membrane and bind in a “tail-up, head-down” orientation to the capsaicin-binding (vanilloid binding) pocket region formed by the S3, S4, and S4–5 linkers of TRPV1 [2,5,75]. Similarly, RTX, an ultrapotent agonist of TRPV1, binds to a location close to Y511 and S512 in S3 and M547 in S4 [36]. In addition, extracellular protons are important physiological stimulators of TRPV1 [92]. Hydrogen-binding sites are located in the outer pore domain of TRPV1 and potentiate the heat sensitivity of TRPV1 [92]. In addition to plant-derived TRPV1 agonists, various animal-derived toxins have been reported to act on the pore region of TRPV1. These act directly or indirectly by stimulating pathways that can sensitize TRPV1 [56,81]. The mechanisms underlying the various pain sensations mediated by TRPV1 are not fully understood. Therefore, investigating the mechanism of TRPV1 activation and the inhibition of both the intracellular vanilloid-binding site and outer pore domain site is important for the discovery of pain inhibitors.

4. Functional Regulation of TRPV1 as a Venom Peptide Target

4.1. Side Effects of TRPV1 Inhibition as a Drug Target

The diverse physiological roles of TRPV1 pose a serious challenge to drug development, notably for obtaining sufficient specificity for clinically useful interventions without undesirable side effects, such as burns and hyperthermia [107]. As TRPV1 is a multimodal ion channel that responds to several stimuli, including heat, low pH, and capsaicin [11], the development of a modality-dependent inhibitor is necessary. For example, antagonists that do not inhibit the thermal activation of TRPV1 do not induce hyperthermia [25]. These inhibitors may still have beneficial effects by blocking other specific receptor modalities activated by low pH or other agonists 108]. Thus, antagonists that selectively block the sensitized state of the channel without blocking basal activity may be free of these side effects [108]. TRPV1 is unique among drug targets because the initial agonist-induced burning sensation is followed by sustained desensitization [109]. Therefore, although capsaicin evokes an initial pain reaction, desensitization to the compound has therapeutic potential as a functional antagonist of TRPV1 [107]. The efficacy of TRPV1 agonists or antagonists in preclinical pain models varies [25,55,107,110,111]. However, different effects in inflammatory and neuropathic pain models have been observed, implying that the TRPV1 targets for pain relief are more diverse [104,111,112,113].

4.2. Minimizing Side Effects of TRPV1 Inhibition as a Drug Target

The magnitude of the analgesic efficacy of TRPV1 activation depends on the various stimuli used [83,114]. TRPV1 is highly unusual in that it can modulate similar or different mechanisms, leading to its antagonists having both hyper- and hypothermic effects [115]. Unlike most TRPV1 antagonists, APHC1 and APHC3 exhibit significant analgesic activity in vivo at a low dose, which causes a moderate decrease in core body temperature [85]. More specifically, APHC1 and APHC3 are highly homologous and differ in 4 of 56 amino acids [95]. However, only APHC3 can inhibit the low-pH-mediated activation of TRPV1 [85,95]. The outer loop domain site at which TRPV1 is bound by these polypeptides (APHC1–3) can affect activation by protons and can be allosterically bound to the capsaicin site [83,86]. In addition, other polypeptides also interact with the outer loop domain of TRPV1 and mediate the pain response [6,80,82]. Therefore, these polypeptide toxins could be used as a new class of TRPV1 modulators with significant analgesic effects and without side effects such as hyperthermia, as well as in drug design templates for pain inhibition.

5. Conclusions

TRPV1 is a polymodal receptor activated by endo- and exoligands, heat, lipids, and voltage, with highly distinct functions not only in the nervous system but also in peripheral tissues. Thus, TRPV1 has become an attractive target for the development of novel pain inhibitors, and several inhibitors of TRPV1 have been developed as new analgesics. However, most of these failed testing during clinical trials in animals and humans owing to their serious side effects, such as hyperthermia and altered thermal sensation. Thus, it is necessary to find TRPV1 antagonists that precisely regulate TRPV1 without adverse effects. The venom peptide is a bioactive component that has been reported to probe pain regulatory mechanisms through various ion channels, including TRPV1. However, despite extensive knowledge concerning the limited number of disulfide structures present in animal venom, numerous families of disulfide-rich venom peptides have not been explored. Therefore, this review described the limitations and potential benefits of studying allosteric coupling between the dual gating mechanism (upper and lower gates) of TRPV1 using peptide toxins targeting the outer pore region of TRPV1 that integrate diverse pain signals from TRPV1 activation. In conclusion, the studies evaluated show that it is possible to develop key pain-related modality-dependent inhibitors of TRPV1 using specific venom peptides.

Author Contributions

Conceptualization, T.B. and C.-K.P.; Formal analysis, S.-M.H.; Funding acquisition, T.B. and C.-K.P.; Resources, T.B. and C.-K.P.; Supervision, T.B. and C.-K.P.; Validation, T.B. and C.-K.P.; Visualization, S.-M.H. and Y.-Y.J.; Writing—Original draft, S.-M.H., Y.-Y.J. and Y.-H.K.; Writing—Review and editing, C.F.C., T.B. and C.-K.P. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by grants from Gachon University (GCU-2018-0687 to C.-K.P.) and from the US National Institutes of Health (NS121946 to T.B.).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Benitez-Angeles, M.; Morales-Lazaro, S.L.; Juarez-Gonzalez, E.; Rosenbaum, T. TRPV1: Structure, Endogenous Agonists, and Mechanisms. Int. J. Mol. Sci. 2020, 21, 3421. [Google Scholar] [CrossRef] [PubMed]
  2. Hazan, A.; Kumar, R.; Matzner, H.; Priel, A. The pain receptor TRPV1 displays agonist-dependent activation stoichiometry. Sci. Rep. 2015, 5, 12278. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Brito, R.; Sheth, S.; Mukherjea, D.; Rybak, L.P.; Ramkumar, V. TRPV1: A Potential Drug Target for Treating Various Diseases. Cells 2014, 3, 517–545. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Szolcsanyi, J.; Sandor, Z. Multisteric TRPV1 nocisensor: A target for analgesics. Trends. Pharm. Sci. 2012, 33, 646–655. [Google Scholar] [CrossRef] [PubMed]
  5. Yang, S.; Yang, F.; Zhang, B.; Lee, B.H.; Li, B.; Luo, L.; Zheng, J.; Lai, R. A bimodal activation mechanism underlies scorpion toxin-induced pain. Sci. Adv. 2017, 3, e1700810. [Google Scholar] [CrossRef] [Green Version]
  6. Geron, M.; Hazan, A.; Priel, A. Animal Toxins Providing Insights into TRPV1 Activation Mechanism. Toxins 2017, 9, 326. [Google Scholar] [CrossRef] [Green Version]
  7. Zhang, F.; Jara-Oseguera, A.; Chang, T.H.; Bae, C.; Hanson, S.M.; Swartz, K.J. Heat activation is intrinsic to the pore domain of TRPV1. Proc. Natl. Acad. Sci. USA 2018, 115, E317–E324. [Google Scholar] [CrossRef] [Green Version]
  8. Liang, R.; Kawabata, Y.; Kawabata, F.; Nishimura, S.; Tabata, S. Differences in the acidic sensitivity of transient receptor potential vanilloid 1 (TRPV1) between chickens and mice. Biochem. Biophys. Res. Commun. 2019, 515, 386–393. [Google Scholar] [CrossRef]
  9. Kumar, R.; Geron, M.; Hazan, A.; Priel, A. Endogenous and Exogenous Vanilloids Evoke Disparate TRPV1 Activation to Produce Distinct Neuronal Responses. Front. Pharm. 2020, 11, 903. [Google Scholar] [CrossRef]
  10. Szallasi, A.; Cruz, F.; Geppetti, P. TRPV1: A therapeutic target for novel analgesic drugs? Trends Mol. Med. 2006, 12, 545–554. [Google Scholar] [CrossRef]
  11. Ryu, S.; Liu, B.; Yao, J.; Fu, Q.; Qin, F. Uncoupling proton activation of vanilloid receptor TRPV1. J. Neurosci. 2007, 27, 12797–12807. [Google Scholar] [CrossRef] [PubMed]
  12. Utkin, Y.N. Animal venom studies: Current benefits and future developments. World J. Biol. Chem. 2015, 6, 28–33. [Google Scholar] [CrossRef] [PubMed]
  13. Chen, N.; Xu, S.; Zhang, Y.; Wang, F. Animal protein toxins: Origins and therapeutic applications. Biophys. Rep. 2018, 4, 233–242. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Bohlen, C.J.; Julius, D. Receptor-targeting mechanisms of pain-causing toxins: How ow? Toxicon 2012, 60, 254–264. [Google Scholar] [CrossRef] [Green Version]
  15. Hardy, M.C.; Cochrane, J.; Allavena, R.E. Venomous and poisonous Australian animals of veterinary importance: A rich source of novel therapeutics. Biomed. Res. Int. 2014, 2014, 671041. [Google Scholar] [CrossRef] [Green Version]
  16. Oliveira, S.M.; Silva, C.R.; Trevisan, G.; Villarinho, J.G.; Cordeiro, M.N.; Richardson, M.; Borges, M.H.; Castro, C.J., Jr.; Gomez, M.V.; Ferreira, J. Antinociceptive effect of a novel armed spider peptide Tx3-5 in pathological pain models in mice. Pflug. Arch. 2016, 468, 881–894. [Google Scholar] [CrossRef]
  17. Siemens, J.; Zhou, S.; Piskorowski, R.; Nikai, T.; Lumpkin, E.A.; Basbaum, A.I.; King, D.; Julius, D. Spider toxins activate the capsaicin receptor to produce inflammatory pain. Nature 2006, 444, 208–212. [Google Scholar] [CrossRef]
  18. Rigo, F.K.; Rossato, M.F.; Trevisan, G.; De Pra, S.D.; Ineu, R.P.; Duarte, M.B.; de Castro, C.J., Jr.; Ferreira, J.; Gomez, M.V. PhKv a toxin isolated from the spider venom induces antinociception by inhibition of cholinesterase activating cholinergic system. Scand. J. Pain 2017, 17, 203–210. [Google Scholar]
  19. Patapoutian, A.; Tate, S.; Woolf, C.J. Transient receptor potential channels: Targeting pain at the source. Nat. Rev. Drug Discov. 2009, 8, 55–68. [Google Scholar] [CrossRef] [Green Version]
  20. Lewis, R.J.; Garcia, M.L. Therapeutic potential of venom peptides. Nat. Rev. Drug Discov. 2003, 2, 790–802. [Google Scholar] [CrossRef]
  21. Vidya, V.; Achar, R.R.; Himathi, M.U.; Akshita, N.; Kameshwar, V.H.; Byrappa, K.; Ramadas, D. Venom peptides—A comprehensive translational perspective in pain management. Curr. Res. Toxicol. 2021, 2, 329–340. [Google Scholar]
  22. Laps, S.; Atamleh, F.; Kamnesky, G.; Sun, H.; Brik, A. General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins. Nat. Commun. 2021, 12, 870. [Google Scholar] [CrossRef] [PubMed]
  23. Nicke, A.; Ulens, C.; Rolland, J.F.; Tsetlin, V.I. Editorial: From Peptide and Protein Toxins to Ion Channel Structure/Function and Drug Design. Front. Pharm. 2020, 11, 548366. [Google Scholar] [CrossRef] [PubMed]
  24. Maxwell, M.; Undheim, E.A.B.; Mobli, M. Secreted Cysteine-Rich Repeat Proteins “SCREPs”: A Novel Multi-Domain Architecture. Front. Pharm. 2018, 9, 1333. [Google Scholar] [CrossRef]
  25. Carnevale, V.; Rohacs, T. TRPV1: A Target for Rational Drug Design. Pharmaceuticals 2016, 9, 52. [Google Scholar] [CrossRef]
  26. Hwang, S.M.; Lee, J.Y.; Park, C.K.; Kim, Y.H. The Role of TRP Channels and PMCA in Brain Disorders: Intracellular Calcium and pH Homeostasis. Front. Cell Dev. Biol. 2021, 9, 584388. [Google Scholar] [CrossRef]
  27. Brederson, J.D.; Kym, P.R.; Szallasi, A. Targeting TRP channels for pain relief. Eur. J. Pharm. 2013, 716, 61–76. [Google Scholar] [CrossRef]
  28. Broad, L.M.; Mogg, A.J.; Beattie, R.E.; Ogden, A.M.; Blanco, M.J.; Bleakman, D. TRP channels as emerging targets for pain therapeutics. Expert Opin. Targets 2009, 13, 69–81. [Google Scholar] [CrossRef]
  29. Gonzalez-Ramirez, R.; Chen, Y.; Liedtke, W.B.; Morales-Lazaro, S.L. TRP Channels and Pain. In Neurobiology of TRP Channels; Emir, T.L.R., Ed.; NCBI: Boca Raton, FL, USA, 2017; pp. 125–147. [Google Scholar]
  30. Marwaha, L.; Bansal, Y.; Singh, R.; Saroj, P.; Bhandari, R.; Kuhad, A. TRP channels: Potential drug target for neuropathic pain. Inflammopharmacology 2016, 24, 305–317. [Google Scholar] [CrossRef]
  31. Karki, T.; Tojkander, S. TRPV Protein Family-From Mechanosensing to Cancer Invasion. Biomolecules 2021, 11, 1019. [Google Scholar] [CrossRef]
  32. Bang, S.; Yoo, S.; Oh, U.; Hwang, S.W. Endogenous lipid-derived ligands for sensory TRP ion channels and their pain modulation. Arch. Pharm. Res. 2010, 33, 1509–1520. [Google Scholar] [CrossRef] [PubMed]
  33. Cortright, D.N.; Szallasi, A. TRP channels and pain. Curr. Pharm. Des. 2009, 15, 1736–1749. [Google Scholar] [CrossRef]
  34. Julius, D. TRP channels and pain. Annu. Rev. Cell Dev. Biol. 2013, 29, 355–384. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Levine, J.D.; Alessandri-Haber, N. TRP channels: Targets for the relief of pain. Biochim. Biophys. Acta 2007, 1772, 989–1003. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Cao, E.; Liao, M.; Cheng, Y.; Julius, D. TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 2013, 504, 113–118. [Google Scholar] [CrossRef] [PubMed]
  37. Duo, L.; Hu, L.; Tian, N.; Cheng, G.; Wang, H.; Lin, Z.; Wang, Y.; Yang, Y. TRPV1 gain-of-function mutation impairs pain and itch sensations in mice. Mol. Pain 2018, 14, 1744806918762031. [Google Scholar] [CrossRef]
  38. Abbas, M.A. Modulation of TRPV1 channel function by natural products in the treatment of pain. Chem. Biol. Interact. 2020, 330, 109178. [Google Scholar] [CrossRef]
  39. Rohacs, T. Phosphoinositide regulation of TRPV1 revisited. Pflug. Arch. 2015, 467, 1851–1869. [Google Scholar] [CrossRef] [Green Version]
  40. Leffler, A.; Fischer, M.J.; Rehner, D.; Kienel, S.; Kistner, K.; Sauer, S.K.; Gavva, N.R.; Reeh, P.W.; Nau, C. The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons. J. Clin. Investig. 2008, 118, 763–776. [Google Scholar] [CrossRef]
  41. Jardin, I.; Lopez, J.J.; Diez, R.; Sanchez-Collado, J.; Cantonero, C.; Albarran, L.; Woodard, G.E.; Redondo, P.C.; Salido, G.M.; Smani, T.; et al. TRPs in Pain Sensation. Front. Physiol. 2017, 8, 392. [Google Scholar] [CrossRef] [Green Version]
  42. Storozhuk, M.V.; Moroz, O.F.; Zholos, A.V. Multifunctional TRPV1 Ion Channels in Physiology and Pathology with Focus on the Brain, Vasculature, and Some Visceral Systems. Biomed. Res. Int. 2019, 2019, 5806321. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Balleza-Tapia, H.; Crux, S.; Andrade-Talavera, Y.; Dolz-Gaiton, P.; Papadia, D.; Chen, G.; Johansson, J.; Fisahn, A. TrpV1 receptor activation rescues neuronal function and network gamma oscillations from Abeta-induced impairment in mouse hippocampus in vitro. Elife 2018, 7, e37703. [Google Scholar] [CrossRef] [PubMed]
  44. Marrone, M.C.; Morabito, A.; Giustizieri, M.; Chiurchiu, V.; Leuti, A.; Mattioli, M.; Marinelli, S.; Riganti, L.; Lombardi, M.; Murana, E.; et al. TRPV1 channels are critical brain inflammation detectors and neuropathic pain biomarkers in mice. Nat. Commun. 2017, 8, 15292. [Google Scholar] [CrossRef] [PubMed]
  45. Silverman, H.A.; Chen, A.; Kravatz, N.L.; Chavan, S.S.; Chang, E.H. Involvement of Neural Transient Receptor Potential Channels in Peripheral Inflammation. Front. Immunol. 2020, 11, 590261. [Google Scholar] [CrossRef] [PubMed]
  46. Gavva, N.R. Body-temperature maintenance as the predominant function of the vanilloid receptor TRPV1. Trends Pharm. Sci. 2008, 29, 550–557. [Google Scholar] [CrossRef] [PubMed]
  47. Du, G.; Tian, Y.; Yao, Z.; Vu, S.; Zheng, J.; Chai, L.; Wang, K.; Yang, S. A specialized pore turret in the mammalian cation channel TRPV1 is responsible for distinct and species-specific heat activation thresholds. J. Biol. Chem. 2020, 295, 9641–9649. [Google Scholar] [CrossRef] [PubMed]
  48. Yonghak, P.; Miyata, S.; Kurganov, E. TRPV1 is crucial for thermal homeostasis in the mouse by heat loss behaviors under warm ambient temperature. Sci. Rep. 2020, 10, 8799. [Google Scholar] [CrossRef]
  49. Xia, R.; Dekermendjian, K.; Lullau, E.; Dekker, N. TRPV1: A therapy target that attracts the pharmaceutical interests. Adv. Exp. Med. Biol. 2011, 704, 637–665. [Google Scholar]
  50. Mishra, S.K.; Tisel, S.M.; Orestes, P.; Bhangoo, S.K.; Hoon, M.A. TRPV1-lineage neurons are required for thermal sensation. EMBO J. 2011, 30, 582–593. [Google Scholar] [CrossRef] [Green Version]
  51. Kwon, D.H.; Zhang, F.; Suo, Y.; Bouvette, J.; Borgnia, M.J.; Lee, S.Y. Heat-dependent opening of TRPV1 in the presence of capsaicin. Nat. Struct. Mol. Biol. 2021, 28, 554–563. [Google Scholar] [CrossRef]
  52. Kasimova, M.A.; Yazici, A.; Yudin, Y.; Granata, D.; Klein, M.L.; Rohacs, T.; Carnevale, V. Ion Channel Sensing: Are Fluctuations the Crux of the Matter? J. Phys. Chem. Lett. 2018, 9, 1260–1264. [Google Scholar] [CrossRef]
  53. Kasimova, M.A.; Yazici, A.T.; Yudin, Y.; Granata, D.; Klein, M.L.; Rohacs, T.; Carnevale, V. A hypothetical molecular mechanism for TRPV1 activation that invokes rotation of an S6 asparagine. J. Gen. Physiol. 2018, 150, 1554–1566. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Geron, M.; Kumar, R.; Zhou, W.; Faraldo-Gomez, J.D.; Vasquez, V.; Priel, A. TRPV1 pore turret dictates distinct DkTx and capsaicin gating. Proc. Natl. Acad. Sci. USA 2018, 115, E11837–E11846. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Hellmich, U.A.; Gaudet, R. High-resolution views of TRPV1 and their implications for the TRP channel superfamily. Handb. Exp. Pharm. 2014, 223, 991–1004. [Google Scholar]
  56. Gladkikh, I.N.; Sintsova, O.V.; Leychenko, E.V.; Kozlov, S.A. TRPV1 Ion Channel: Structural Features, Activity Modulators, and Therapeutic Potential. Biochemistry 2021, 86 (Suppl. 1), S50–S70. [Google Scholar] [CrossRef]
  57. Winter, Z.; Buhala, A.; Otvos, F.; Josvay, K.; Vizler, C.; Dombi, G.; Szakonyi, G.; Olah, Z. Functionally important amino acid residues in the transient receptor potential vanilloid 1 (TRPV1) ion channel—An overview of the current mutational data. Mol. Pain 2013, 9, 30. [Google Scholar] [CrossRef] [Green Version]
  58. King, G.F. Venoms as a platform for human drugs: Translating toxins into therapeutics. Expert Opin. Biol. 2011, 11, 1469–1484. [Google Scholar] [CrossRef]
  59. Chen, Y.N.; Li, K.C.; Li, Z.; Shang, G.W.; Liu, D.N.; Lu, Z.M.; Zhang, J.W.; Ji, Y.H.; Gao, G.D.; Chen, J. Effects of bee venom peptidergic components on rat pain-related behaviors and inflammation. Neuroscience 2006, 138, 631–640. [Google Scholar] [CrossRef]
  60. Herzig, V.; Cristofori-Armstrong, B.; Israel, M.R.; Nixon, S.A.; Vetter, I.; King, G.F. Animal toxins—Nature’s evolutionary-refined toolkit for basic research and drug discovery. Biochem. Pharm. 2020, 181, 114096. [Google Scholar] [CrossRef]
  61. Pineda, S.S.; Chin, Y.K.; Undheim, E.A.B.; Senff, S.; Mobli, M.; Dauly, C.; Escoubas, P.; Nicholson, G.M.; Kaas, Q.; Guo, S.; et al. Structural venomics reveals evolution of a complex venom by duplication and diversification of an ancient peptide-encoding gene. Proc. Natl. Acad. Sci. USA 2020, 117, 11399–11408. [Google Scholar] [CrossRef]
  62. Craik, D.J.; Daly, N.L.; Waine, C. The cystine knot motif in toxins and implications for drug design. Toxicon 2001, 39, 43–60. [Google Scholar] [CrossRef]
  63. Menez, A. Functional architectures of animal toxins: A clue to drug design? Toxicon 1998, 36, 1557–1572. [Google Scholar] [CrossRef]
  64. Rosengren, K.J.; Daly, N.L.; Plan, M.R.; Waine, C.; Craik, D.J. Twists, knots, and rings in proteins. Structural definition of the cyclotide framework. J. Biol. Chem. 2003, 278, 8606–8616. [Google Scholar] [CrossRef] [Green Version]
  65. Iyer, S.; Acharya, K.R. Tying the knot: The cystine signature and molecular-recognition processes of the vascular endothelial growth factor family of angiogenic cytokines. FEBS J. 2011, 278, 4304–4322. [Google Scholar] [CrossRef] [Green Version]
  66. Kimura, T. Stability and Safety of Inhibitor Cystine Knot Peptide, GTx1-15, from the Tarantula Spider Grammostola rosea. Toxins 2021, 13, 621. [Google Scholar] [CrossRef]
  67. Wu, T.; Wang, M.; Wu, W.; Luo, Q.; Jiang, L.; Tao, H.; Deng, M. Spider venom peptides as potential drug candidates due to their anticancer and antinociceptive activities. J. Venom. Anim. Toxins Incl. Trop. Dis. 2019, 25, e146318. [Google Scholar] [CrossRef]
  68. Bae, C.; Anselmi, C.; Kalia, J.; Jara-Oseguera, A.; Schwieters, C.D.; Krepkiy, D.; Won Lee, C.; Kim, E.H.; Kim, J.I.; Faraldo-Gomez, J.D.; et al. Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin. Elife 2016, 5, e11273. [Google Scholar] [CrossRef]
  69. Bae, C.; Kalia, J.; Song, I.; Yu, J.; Kim, H.H.; Swartz, K.J.; Kim, J.I. High yield production and refolding of the double-knot toxin, an activator of TRPV1 channels. PLoS ONE 2012, 7, e51516. [Google Scholar] [CrossRef] [Green Version]
  70. Bohlen, C.J.; Priel, A.; Zhou, S.; King, D.; Siemens, J.; Julius, D. A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain. Cell 2010, 141, 834–845. [Google Scholar] [CrossRef] [Green Version]
  71. Mihailescu, M.; Krepkiy, D.; Milescu, M.; Gawrisch, K.; Swartz, K.J.; White, S. Structural interactions of a voltage sensor toxin with lipid membranes. Proc. Natl. Acad. Sci. USA 2014, 111, E5463–E5470. [Google Scholar] [CrossRef] [Green Version]
  72. Yang, F.; Xu, L.; Lee, B.H.; Xiao, X.; Yarov-Yarovoy, V.; Zheng, J. An Unorthodox Mechanism Underlying Voltage Sensitivity of TRPV1 Ion Channel. Adv. Sci. 2020, 7, 2000575. [Google Scholar] [CrossRef]
  73. Elokely, K.; Velisetty, P.; Delemotte, L.; Palovcak, E.; Klein, M.L.; Rohacs, T.; Carnevale, V. Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin. Proc. Natl. Acad. Sci. USA 2016, 113, E137–E145. [Google Scholar] [CrossRef] [Green Version]
  74. Vu, S.; Singh, V.; Wulff, H.; Yarov-Yarovoy, V.; Zheng, J. New capsaicin analogs as molecular rulers to define the permissive conformation of the mouse TRPV1 ligand-binding pocket. Elife 2020, 9, e62039. [Google Scholar] [CrossRef]
  75. Chu, Y.; Cohen, B.E.; Chuang, H.H. A single TRPV1 amino acid controls species sensitivity to capsaicin. Sci. Rep. 2020, 10, 8038. [Google Scholar] [CrossRef]
  76. Nadezhdin, K.D.; Neuberger, A.; Nikolaev, Y.A.; Murphy, L.A.; Gracheva, E.O.; Bagriantsev, S.N.; Sobolevsky, A.I. Extracellular cap domain is an essential component of the TRPV1 gating mechanism. Nat. Commun. 2021, 12, 2154. [Google Scholar] [CrossRef]
  77. Gao, Y.; Cao, E.; Julius, D.; Cheng, Y. TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. Nature 2016, 534, 347–351. [Google Scholar] [CrossRef] [Green Version]
  78. Sarkar, D.; Singh, Y.; Kalia, J. Protein-Lipid Interfaces Can Drive the Functions of Membrane-Embedded Protein-Protein Complexes. ACS Chem. Biol. 2018, 13, 2689–2698. [Google Scholar] [CrossRef] [Green Version]
  79. Yang, S.; Yang, F.; Wei, N.; Hong, J.; Li, B.; Luo, L.; Rong, M.; Yarov-Yarovoy, V.; Zheng, J.; Wang, K.; et al. A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1. Nat. Commun. 2015, 6, 8297. [Google Scholar] [CrossRef] [Green Version]
  80. Zhu, A.; Aierken, A.; Yao, Z.; Vu, S.; Tian, Y.; Zheng, J.; Yang, S.; Yang, F. A centipede toxin causes rapid desensitization of nociceptor TRPV1 ion channel. Toxicon 2020, 178, 41–49. [Google Scholar] [CrossRef]
  81. Zheng, J.; Ma, L. Structure and function of the thermoTRP channel pore. Curr. Top. Membr. 2014, 74, 233–257. [Google Scholar]
  82. Hakim, M.A.; Jiang, W.; Luo, L.; Li, B.; Yang, S.; Song, Y.; Lai, R. Scorpion Toxin, BmP01, Induces Pain by Targeting TRPV1 Channel. Toxins 2015, 7, 3671–3687. [Google Scholar] [CrossRef] [Green Version]
  83. Nikolaev, M.V.; Dorofeeva, N.A.; Komarova, M.S.; Korolkova, Y.V.; Andreev, Y.A.; Mosharova, I.V.; Grishin, E.V.; Tikhonov, D.B.; Kozlov, S.A. TRPV1 activation power can switch an action mode for its polypeptide ligands. PLoS ONE 2017, 12, e0177077. [Google Scholar] [CrossRef]
  84. Andreev, Y.A.; Kozlov, S.A.; Koshelev, S.G.; Ivanova, E.A.; Monastyrnaya, M.M.; Kozlovskaya, E.P.; Grishin, E.V. Analgesic compound from sea anemone Heteractis crispa is the first polypeptide inhibitor of vanilloid receptor 1 (TRPV1). J. Biol. Chem. 2008, 283, 23914–23921. [Google Scholar] [CrossRef] [Green Version]
  85. Andreev, Y.A.; Kozlov, S.A.; Korolkova, Y.V.; Dyachenko, I.A.; Bondarenko, D.A.; Skobtsov, D.I.; Murashev, A.N.; Kotova, P.D.; Rogachevskaja, O.A.; Kabanova, N.V.; et al. Polypeptide modulators of TRPV1 produce analgesia without hyperthermia. Mar. Drugs 2013, 11, 5100–5115. [Google Scholar] [CrossRef] [Green Version]
  86. Dyachenko, I.A.; Andreev, Y.A.; Logashina, Y.A.; Murashev, A.N.; Grishin, E.V. Biological activity of a polypeptide modulator of TRPV1 receptor. Dokl. Biol. Sci. 2015, 465, 279–281. [Google Scholar] [CrossRef]
  87. Monastyrnaya, M.; Peigneur, S.; Zelepuga, E.; Sintsova, O.; Gladkikh, I.; Leychenko, E.; Isaeva, M.; Tytgat, J.; Kozlovskaya, E. Kunitz-Type Peptide HCRG21 from the Sea Anemone Heteractis crispa Is a Full Antagonist of the TRPV1 Receptor. Mar. Drugs 2016, 14, 229. [Google Scholar] [CrossRef]
  88. Sintsova, O.; Gladkikh, I.; Klimovich, A.; Palikova, Y.; Palikov, V.; Styshova, O.; Monastyrnaya, M.; Dyachenko, I.; Kozlov, S.; Leychenko, E. TRPV1 Blocker HCRG21 Suppresses TNF-alpha Production and Prevents the Development of Edema and Hypersensitivity in Carrageenan-Induced Acute Local Inflammation. Biomedicines 2021, 9, 716. [Google Scholar] [CrossRef]
  89. Peigneur, S.; Tytgat, J. Toxins in Drug Discovery and Pharmacology. Toxins 2018, 10, 126. [Google Scholar] [CrossRef] [Green Version]
  90. Diochot, S. Pain-related toxins in scorpion and spider venoms: A face to face with ion channels. J. Venom. Anim. Toxins Incl. Trop. Dis. 2021, 27, e20210026. [Google Scholar] [CrossRef]
  91. Karbat, I.; Altman-Gueta, H.; Fine, S.; Szanto, T.; Hamer-Rogotner, S.; Dym, O.; Frolow, F.; Gordon, D.; Panyi, G.; Gurevitz, M.; et al. Pore-modulating toxins exploit inherent slow inactivation to block K(+) channels. Proc. Natl. Acad. Sci. USA 2019, 116, 18700–18709. [Google Scholar] [CrossRef] [Green Version]
  92. Nie, Y.; Li, Y.; Liu, L.; Ren, S.; Tian, Y.; Yang, F. Molecular mechanism underlying modulation of TRPV1 heat activation by polyols. J. Biol. Chem. 2021, 297, 100806. [Google Scholar] [CrossRef] [PubMed]
  93. Yang, F.; Zheng, J. Understand spiciness: Mechanism of TRPV1 channel activation by capsaicin. Protein Cell 2017, 8, 169–177. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Wen, H.; Zheng, W. Decrypting the Heat Activation Mechanism of TRPV1 Channel by Molecular Dynamics Simulation. Biophys. J. 2018, 114, 40–52. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Diaz-Franulic, I.; Caceres-Molina, J.; Sepulveda, R.V.; Gonzalez-Nilo, F.; Latorre, R. Structure-Driven Pharmacology of Transient Receptor Potential Channel Vanilloid 1. Mol. Pharm. 2016, 90, 300–308. [Google Scholar] [CrossRef]
  96. Cromer, B.A.; McIntyre, P. Painful toxins acting at TRPV1. Toxicon 2008, 51, 163–173. [Google Scholar] [CrossRef] [Green Version]
  97. Premkumar, L.S. Targeting TRPV1 as an alternative approach to narcotic analgesics to treat chronic pain conditions. AAPS J. 2010, 12, 361–370. [Google Scholar] [CrossRef] [Green Version]
  98. Cortright, D.N.; Krause, J.E.; Broom, D.C. TRP channels and pain. Biochim. Biophys. Acta 2007, 1772, 978–988. [Google Scholar] [CrossRef] [Green Version]
  99. Boukalova, S.; Teisinger, J.; Vlachova, V. Protons stabilize the closed conformation of gain-of-function mutants of the TRPV1 channel. Biochim. Biophys. Acta 2013, 1833, 520–528. [Google Scholar] [CrossRef] [Green Version]
  100. Yang, F.; Xiao, X.; Lee, B.H.; Vu, S.; Yang, W.; Yarov-Yarovoy, V.; Zheng, J. The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel. Nat. Commun. 2018, 9, 2879. [Google Scholar] [CrossRef]
  101. Zheng, W.; Wen, H. Heat activation mechanism of TRPV1: New insights from molecular dynamics simulation. Temperature 2019, 6, 120–131. [Google Scholar] [CrossRef] [Green Version]
  102. Chu, Y.; Qiu, P.; Yu, R. Centipede Venom Peptides Acting on Ion Channels. Toxins 2020, 12, 230. [Google Scholar] [CrossRef] [Green Version]
  103. Velisetty, P.; Stein, R.A.; Sierra-Valdez, F.J.; Vasquez, V.; Cordero-Morales, J.F. Expression and Purification of the Pain Receptor TRPV1 for Spectroscopic Analysis. Sci. Rep. 2017, 7, 9861. [Google Scholar] [CrossRef] [PubMed]
  104. Szallasi, A.; Cortright, D.N.; Blum, C.A.; Eid, S.R. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat. Rev. Drug Discov. 2007, 6, 357–372. [Google Scholar] [CrossRef] [PubMed]
  105. Goswami, C.; Schmidt, H.; Hucho, F. TRPV1 at nerve endings regulates growth cone morphology and movement through cytoskeleton reorganization. FEBS J. 2007, 274, 760–772. [Google Scholar] [CrossRef] [PubMed]
  106. Frias, B.; Merighi, A. Capsaicin, Nociception and Pain. Molecules 2016, 21, 797. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Koivisto, A.P.; Belvisi, M.G.; Gaudet, R.; Szallasi, A. Advances in TRP channel drug discovery: From target validation to clinical studies. Nat. Rev. Drug. Discov. 2021, 21, 1–19. [Google Scholar] [CrossRef]
  108. Huang, S.; Szallasi, A. Transient Receptor Potential (TRP) Channels in Drug Discovery: Old Concepts & New Thoughts. Pharmaceuticals 2017, 10, 64. [Google Scholar]
  109. Szymaszkiewicz, A.; Wlodarczyk, J.; Wasilewski, A.; Di Marzo, V.; Storr, M.; Fichna, J.; Zielinska, M. Desensitization of transient receptor potential vanilloid type-1 (TRPV1) channel as promising therapy of irritable bowel syndrome: Characterization of the action of palvanil in the mouse gastrointestinal tract. Naunyn. Schmiedebergs. Arch. Pharm. 2020, 393, 1357–1364. [Google Scholar] [CrossRef] [Green Version]
  110. Szallasi, A.; Sheta, M. Targeting TRPV1 for pain relief: Limits, losers and laurels. Expert Opin. Investig. Drugs 2012, 21, 1351–1369. [Google Scholar] [CrossRef]
  111. Gunthorpe, M.J.; Chizh, B.A. Clinical development of TRPV1 antagonists: Targeting a pivotal point in the pain pathway. Drug Discov. Today 2009, 14, 56–67. [Google Scholar] [CrossRef]
  112. Gavva, N.R.; Bannon, A.W.; Hovland, D.N., Jr.; Lehto, S.G.; Klionsky, L.; Surapaneni, S.; Immke, D.C.; Henley, C.; Arik, L.; Bak, A.; et al. Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade. J. Pharm. Exp. 2007, 323, 128–137. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Garami, A.; Shimansky, Y.P.; Pakai, E.; Oliveira, D.L.; Gavva, N.R.; Romanovsky, A.A. Contributions of different modes of TRPV1 activation to TRPV1 antagonist-induced hyperthermia. J. Neurosci. 2010, 30, 1435–1440. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Garami, A.; Shimansky, Y.P.; Rumbus, Z.; Vizin, R.C.L.; Farkas, N.; Hegyi, J.; Szakacs, Z.; Solymar, M.; Csenkey, A.; Chiche, D.A.; et al. Hyperthermia induced by transient receptor potential vanilloid-1 (TRPV1) antagonists in human clinical trials: Insights from mathematical modeling and meta-analysis. Pharmacol. Ther. 2020, 208, 107474. [Google Scholar] [CrossRef] [PubMed]
  115. Garami, A.; Pakai, E.; McDonald, H.A.; Reilly, R.M.; Gomtsyan, A.; Corrigan, J.J.; Pinter, E.; Zhu, D.X.D.; Lehto, S.G.; Gavva, N.R.; et al. TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development. Acta. Physiol. 2018, 223, e13038. [Google Scholar] [CrossRef] [Green Version]
Ijms 23 05772 g001 550
Figure 1. The structure and binding sites of the transient receptor potential vanilloid 1 (TRPV1) channel. (A) TRPV1 is a homotetrameric transmembrane protein containing a voltage-sensory domain, pore domain, S4–5 helix linker, and TRP box. The N-terminal end comprises ankyrin repeats and a calmodulin interaction site, while the C-terminal end contains a PIP2 interaction site. Amino acid residues at both ends can be phosphorylated by PKC and PKA. Vanilloid agonist sites are located in the S2–4 transmembrane domain. Both heat- and protein-initiated stimuli are mediated by specific residues located in the extracellular membrane domain (or loops). The selectivity filter is formed by the loop connecting the pore helix and S6 helix. The large and small turret subunits are connected to the S5 and S6 domains. The outer pore domain is indicated by a red dashed circle. (B) Side view of the TRPV1 structure: the tetrameric structure of the pore helix and the upper and lower gates, which regulate channel activation. The vanilloid pocket region is highlighted by the black box, and the pore helix is indicated by a black dashed circle (PBD ID: 7LQZ). (C) Top view of the TRPV1 structure: the outer pore region is highlighted by a red box, and the pore region is indicated by a black circle (PBD ID: 7LQZ). The symbols beneath each 3D structure are the access numbers in the Protein Data Bank (PDB). (D) Side view of a single TRPV1 subunit color coded as described in B (PDB ID: 7L2S). Sequence alignment of rat TRPV1 construct (NW_024405602); linker domain, pre-S1 helix (linker), S1–6, outer pore domain, and TRP are highlighted in purple, yellow, green, dark blue, and light blue, respectively. (E) Side view of the TRPV1 tetrameric structure (PDB ID: 7L2S) showing the outer pore binding venom peptides (DkTx, RhTx, and APHC) and their sites (orange box). Similarly, vanilloid binding agonist (capsaicin and RTX) and its site (black box) are shown.
Figure 1. The structure and binding sites of the transient receptor potential vanilloid 1 (TRPV1) channel. (A) TRPV1 is a homotetrameric transmembrane protein containing a voltage-sensory domain, pore domain, S4–5 helix linker, and TRP box. The N-terminal end comprises ankyrin repeats and a calmodulin interaction site, while the C-terminal end contains a PIP2 interaction site. Amino acid residues at both ends can be phosphorylated by PKC and PKA. Vanilloid agonist sites are located in the S2–4 transmembrane domain. Both heat- and protein-initiated stimuli are mediated by specific residues located in the extracellular membrane domain (or loops). The selectivity filter is formed by the loop connecting the pore helix and S6 helix. The large and small turret subunits are connected to the S5 and S6 domains. The outer pore domain is indicated by a red dashed circle. (B) Side view of the TRPV1 structure: the tetrameric structure of the pore helix and the upper and lower gates, which regulate channel activation. The vanilloid pocket region is highlighted by the black box, and the pore helix is indicated by a black dashed circle (PBD ID: 7LQZ). (C) Top view of the TRPV1 structure: the outer pore region is highlighted by a red box, and the pore region is indicated by a black circle (PBD ID: 7LQZ). The symbols beneath each 3D structure are the access numbers in the Protein Data Bank (PDB). (D) Side view of a single TRPV1 subunit color coded as described in B (PDB ID: 7L2S). Sequence alignment of rat TRPV1 construct (NW_024405602); linker domain, pre-S1 helix (linker), S1–6, outer pore domain, and TRP are highlighted in purple, yellow, green, dark blue, and light blue, respectively. (E) Side view of the TRPV1 tetrameric structure (PDB ID: 7L2S) showing the outer pore binding venom peptides (DkTx, RhTx, and APHC) and their sites (orange box). Similarly, vanilloid binding agonist (capsaicin and RTX) and its site (black box) are shown.
Ijms 23 05772 g001
Table
Table 1. Various ligands and venom peptides (activators/inhibitors) of the transient receptor potential vanilloid 1 (TRPV1) channel.
Table 1. Various ligands and venom peptides (activators/inhibitors) of the transient receptor potential vanilloid 1 (TRPV1) channel.
LigandsBinding RegionBinding TypePain ConditionReference
CapsaicinVanilloid-binding pocketHydrogen, Van der Waals bondPain sensation[73,74,75]
RTXVanilloid-binding pocketHydrogen bondPain sensation[73,76]
ProtonOuter pore domainHydrogen bondPain sensation[36]
Double-knot toxin (DkTx)Outer pore domainHydrophobic interactionPain sensation[6,54,68,70,71,77,78]
Vanillotoxins (VaTx1–3)Outer pore domainElectrostatic interactionPain sensation[5,6,14]
Scolopendra subspinipes mutilans toxin RhTxOuter pore domainElectrostatic and hydrophobic interactionsPain sensation[2,79,80]
Pain-inducing peptide (BmP01)Outer pore domainElectrostatic interactionPain sensation[5,81,82]
Analgesic polypeptide Heteractis crispa (APHC) toxinOuter pore domainNo direct evidenceAnalgesic action[83,84,85,86]
Heteractis crispa RG 21 (HCRG21)Outer pore domainNo direct evidenceAnalgesic action[87,88]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Hwang, S.-M.; Jo, Y.-Y.; Cohen, C.F.; Kim, Y.-H.; Berta, T.; Park, C.-K. Venom Peptide Toxins Targeting the Outer Pore Region of Transient Receptor Potential Vanilloid 1 in Pain: Implications for Analgesic Drug Development. Int. J. Mol. Sci. 2022, 23, 5772. https://doi.org/10.3390/ijms23105772

AMA Style

Hwang S-M, Jo Y-Y, Cohen CF, Kim Y-H, Berta T, Park C-K. Venom Peptide Toxins Targeting the Outer Pore Region of Transient Receptor Potential Vanilloid 1 in Pain: Implications for Analgesic Drug Development. International Journal of Molecular Sciences. 2022; 23(10):5772. https://doi.org/10.3390/ijms23105772

Chicago/Turabian Style

Hwang, Sung-Min, Youn-Yi Jo, Cinder Faith Cohen, Yong-Ho Kim, Temugin Berta, and Chul-Kyu Park. 2022. "Venom Peptide Toxins Targeting the Outer Pore Region of Transient Receptor Potential Vanilloid 1 in Pain: Implications for Analgesic Drug Development" International Journal of Molecular Sciences 23, no. 10: 5772. https://doi.org/10.3390/ijms23105772

APA Style

Hwang, S. -M., Jo, Y. -Y., Cohen, C. F., Kim, Y. -H., Berta, T., & Park, C. -K. (2022). Venom Peptide Toxins Targeting the Outer Pore Region of Transient Receptor Potential Vanilloid 1 in Pain: Implications for Analgesic Drug Development. International Journal of Molecular Sciences, 23(10), 5772. https://doi.org/10.3390/ijms23105772

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop