International Journal of Molecular Sciences

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21 pages, 4295 KiB

Open AccessArticle

Activation of the TRPML1 Ion Channel Induces Proton Secretion in the Human Gastric Parietal Cell Line HGT-1

by Alina Ulrike Mueller, Gaby Andersen, Phil Richter and Veronika Somoza

Int. J. Mol. Sci. 2024, 25(16), 8829; https://doi.org/10.3390/ijms25168829 - 13 Aug 2024

Viewed by 1137

Abstract

The lysosomal Ca²⁺ channel TRPML1 was found to be responsible for gastric acid secretion in murine gastric parietal cells by inducing the trafficking of H⁺/K⁺-ATPase containing tubulovesicles to the apical membrane. Therefore, we hypothesized a similar role of [...] Read more.

The lysosomal Ca²⁺ channel TRPML1 was found to be responsible for gastric acid secretion in murine gastric parietal cells by inducing the trafficking of H⁺/K⁺-ATPase containing tubulovesicles to the apical membrane. Therefore, we hypothesized a similar role of TRPML1 in regulating proton secretion in the immortalized human parietal cell line HGT-1. The primary focus was to investigate the involvement of TRPML1 in proton secretion using the known synthetic agonists ML-SA1 and ML-SA5 and the antagonist ML-SI3 and, furthermore, to identify food-derived compounds that target the channel. Proton secretion stimulated by ML-SA1 was reduced by 122.2 ± 22.7% by the antagonist ML-SI3. The steroid hormone 17β-estradiol, present in animal-derived foods, diminished the proton secretory effect of ML-SA1 by 63.4 ± 14.5%. We also demonstrated a reduction in the proton secretory effects of ML-SA1 and ML-SA5 on TRPML1 knock-down cells. The food-derived compounds sulforaphane and trehalose promoted proton secretion in HGT-1 cells but may act independently of TRPML1. Also, histamine- and caffeine-induced proton secretion were affected by neither the TRPML1 antagonist ML-SI3 nor the TRPML1 knock-down. In summary, the results obtained suggest that the activation of TRPML1 promotes proton secretion in HGT-1 cells, but the channel may not participate in canonical signaling pathways. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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18 pages, 6676 KiB

Open AccessArticle

Selective Assembly of TRPC Channels in the Rat Retina during Photoreceptor Degeneration

by Elena Caminos, Susana López-López and Juan R. Martinez-Galan

Int. J. Mol. Sci. 2024, 25(13), 7251; https://doi.org/10.3390/ijms25137251 - 30 Jun 2024

Viewed by 1100

Abstract

Transient receptor potential canonical (TRPC) channels are calcium channels with diverse expression profiles and physiological implications in the retina. Neurons and glial cells of rat retinas with photoreceptor degeneration caused by retinitis pigmentosa (RP) exhibit basal calcium levels that are above those detected [...] Read more.

Transient receptor potential canonical (TRPC) channels are calcium channels with diverse expression profiles and physiological implications in the retina. Neurons and glial cells of rat retinas with photoreceptor degeneration caused by retinitis pigmentosa (RP) exhibit basal calcium levels that are above those detected in healthy retinas. Inner retinal cells are the last to degenerate and are responsible for maintaining the activity of the visual cortex, even after complete loss of photoreceptors. We considered the possibility that TRPC1 and TRPC5 channels might be associated with both the high calcium levels and the delay in inner retinal degeneration. TRPC1 is known to mediate protective effects in neurodegenerative processes while TRPC5 promotes cell death. In order to comprehend the implications of these channels in RP, the co-localization and subsequent physical interaction between TRPC1 and TRPC5 in healthy retina (Sprague-Dawley rats) and degenerating (P23H-1, a model of RP) retina were detected by immunofluorescence and proximity ligation assays. There was an overlapping signal in the innermost retina of all animals where TRPC1 and TRPC5 physically interacted. This interaction increased significantly as photoreceptor loss progressed. Both channels function as TRPC1/5 heteromers in the healthy and damaged retina, with a marked function of TRPC1 in response to retinal degenerative mechanisms. Furthermore, our findings support that TRPC5 channels also function in partnership with STIM1 in Müller and retinal ganglion cells. These results suggest that an increase in TRPC1/5 heteromers may contribute to the slowing of the degeneration of the inner retina during the outer retinal degeneration. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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18 pages, 4475 KiB

Open AccessArticle

In Silico Electrophysiological Investigation of Transient Receptor Potential Melastatin-4 Ion Channel Biophysics to Study Detrusor Overactivity

by Chitaranjan Mahapatra and Ravindra Thakkar

Int. J. Mol. Sci. 2024, 25(13), 6875; https://doi.org/10.3390/ijms25136875 - 22 Jun 2024

Cited by 1 | Viewed by 814

Abstract

Enhanced electrical activity in detrusor smooth muscle (DSM) cells is a key factor in detrusor overactivity which causes overactive bladder pathological disorders. Transient receptor potential melastatin-4 (TRPM4) channels, which are calcium-activated cation channels, play a role in regulating DSM electrical activities. These channels [...] Read more.

Enhanced electrical activity in detrusor smooth muscle (DSM) cells is a key factor in detrusor overactivity which causes overactive bladder pathological disorders. Transient receptor potential melastatin-4 (TRPM4) channels, which are calcium-activated cation channels, play a role in regulating DSM electrical activities. These channels likely contribute to depolarizing the DSM cell membrane, leading to bladder overactivity. Our research focuses on understanding TRPM4 channel function in the DSM cells of mice, using computational modeling. We aimed to create a detailed computational model of the TRPM4 channel based on existing electrophysiological data. We employed a modified Hodgkin-Huxley model with an incorporated TRP-like current to simulate action potential firing in response to current and synaptic stimulus inputs. Validation against experimental data showed close agreement with our simulations. Our model is the first to analyze the TRPM4 channel’s role in DSM electrical activity, potentially revealing insights into bladder overactivity. In conclusion, TRPM4 channels are pivotal in regulating human DSM function, and TRPM4 channel inhibitors could be promising targets for treating overactive bladder. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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19 pages, 6608 KiB

Open AccessArticle

Effect of TRPV4 Antagonist GSK2798745 on Chlorine Gas-Induced Acute Lung Injury in a Swine Model

by Meghan S. Vermillion, Nathan Saari, Mathieu Bray, Andrew M. Nelson, Robert L. Bullard, Karin Rudolph, Andrew P. Gigliotti, Jeffrey Brendler, Jacob Jantzi, Philip J. Kuehl, Jacob D. McDonald, Mark E. Burgert, Waylon Weber, Scott Sucoloski and David J. Behm

Int. J. Mol. Sci. 2024, 25(7), 3949; https://doi.org/10.3390/ijms25073949 - 2 Apr 2024

Cited by 3 | Viewed by 1345

Abstract

As a regulator of alveolo-capillary barrier integrity, Transient Receptor Potential Vanilloid 4 (TRPV4) antagonism represents a promising strategy for reducing pulmonary edema secondary to chemical inhalation. In an experimental model of acute lung injury induced by exposure of anesthetized swine to chlorine gas [...] Read more.

As a regulator of alveolo-capillary barrier integrity, Transient Receptor Potential Vanilloid 4 (TRPV4) antagonism represents a promising strategy for reducing pulmonary edema secondary to chemical inhalation. In an experimental model of acute lung injury induced by exposure of anesthetized swine to chlorine gas by mechanical ventilation, the dose-dependent effects of TRPV4 inhibitor GSK2798745 were evaluated. Pulmonary function and oxygenation were measured hourly; airway responsiveness, wet-to-dry lung weight ratios, airway inflammation, and histopathology were assessed 24 h post-exposure. Exposure to 240 parts per million (ppm) chlorine gas for ≥50 min resulted in acute lung injury characterized by sustained changes in the ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration (PaO₂/FiO₂), oxygenation index, peak inspiratory pressure, dynamic lung compliance, and respiratory system resistance over 24 h. Chlorine exposure also heightened airway response to methacholine and increased wet-to-dry lung weight ratios at 24 h. Following 55-min chlorine gas exposure, GSK2798745 marginally improved PaO₂/FiO₂, but did not impact lung function, airway responsiveness, wet-to-dry lung weight ratios, airway inflammation, or histopathology. In summary, in this swine model of chlorine gas-induced acute lung injury, GSK2798745 did not demonstrate a clinically relevant improvement of key disease endpoints. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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15 pages, 2249 KiB

Open AccessArticle

Pharmacological Activation of TRPC6 Channel Prevents Colitis Progression

by Kazuhiro Nishiyama, Yuri Kato, Akiyuki Nishimura, Xinya Mi, Ryu Nagata, Yasuo Mori, Yasu-Taka Azuma and Motohiro Nishida

Int. J. Mol. Sci. 2024, 25(4), 2401; https://doi.org/10.3390/ijms25042401 - 18 Feb 2024

Cited by 1 | Viewed by 1598

Abstract

We recently reported that transient receptor potential canonical (TRPC) 6 channel activity contributes to intracellular Zn²⁺ homeostasis in the heart. Zn²⁺ has also been implicated in the regulation of intestinal redox and microbial homeostasis. This study aims to investigate the role [...] Read more.

We recently reported that transient receptor potential canonical (TRPC) 6 channel activity contributes to intracellular Zn²⁺ homeostasis in the heart. Zn²⁺ has also been implicated in the regulation of intestinal redox and microbial homeostasis. This study aims to investigate the role of TRPC6-mediated Zn²⁺ influx in the stress resistance of the intestine. The expression profile of TRPC1-C7 mRNAs in the actively inflamed mucosa from inflammatory bowel disease (IBD) patients was analyzed using the GEO database. Systemic TRPC3 knockout (KO) and TRPC6 KO mice were treated with dextran sulfate sodium (DSS) to induce colitis. The Zn²⁺ concentration and the mRNA expression levels of oxidative/inflammatory markers in colon tissues were quantitatively analyzed, and gut microbiota profiles were compared. TRPC6 mRNA expression level was increased in IBD patients and DSS-treated mouse colon tissues. DSS-treated TRPC6 KO mice, but not TRPC3 KO mice, showed severe weight loss and increased disease activity index compared with DSS-treated WT mice. The mRNA abundances of antioxidant proteins were basically increased in the TRPC6 KO colon, with changes in gut microbiota profiles. Treatment with TRPC6 activator prevented the DSS-induced colitis progression accompanied by increasing Zn²⁺ concentration. We suggest that TRPC6-mediated Zn²⁺ influx activity plays a key role in stress resistance against IBD, providing a new strategy for treating colitis. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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11 pages, 3128 KiB

Open AccessArticle

The Lack of TRPA1 Ion Channel Does Not Affect the Chronic Stress-Induced Activation of the Locus Ceruleus

by Milica Milicic, Balázs Gaszner, Gergely Berta, Erika Pintér and Viktória Kormos

Int. J. Mol. Sci. 2024, 25(3), 1765; https://doi.org/10.3390/ijms25031765 - 1 Feb 2024

Cited by 2 | Viewed by 1165

Abstract

We have previously proven the involvement of transient receptor potential ankyrin 1 (TRPA1) in stress adaptation. A lack of TRPA1 affects both urocortin 1 (member of the corticotropin-releasing hormone (CRH) family) content of the Edinger–Westphal nucleus. The noradrenergic locus ceruleus (LC) is also [...] Read more.

We have previously proven the involvement of transient receptor potential ankyrin 1 (TRPA1) in stress adaptation. A lack of TRPA1 affects both urocortin 1 (member of the corticotropin-releasing hormone (CRH) family) content of the Edinger–Westphal nucleus. The noradrenergic locus ceruleus (LC) is also an important player in mood control. We aimed at investigating whether the TRPA1 is expressed in the LC, and to test if the response to chronic variable mild stress (CVMS) is affected by a lack of TRPA1. The TRPA1 expression was examined via RNAscope in situ hybridization. We investigated TRPA1 knockout and wildtype mice using the CVMS model of depression. Tyrosine hydroxylase (TH) and FOSB double immunofluorescence were used to test the functional neuromorphological changes in the LC. No TRPA1 expression was detected in the LC. The TH content was not affected by CVMS exposure. The CVMS-induced FOSB immunosignal did not co-localize with the TH neurons. TRPA1 is not expressed in the LC. A lack of functional TRPA1 receptor neither directly nor indirectly affects the TH content of LC neurons under CVMS. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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17 pages, 3089 KiB

Open AccessArticle

Joint CB1 and NGF Receptor Activation Suppresses TRPM8 Activation in Etoposide-Resistant Retinoblastoma Cells

by Szymon Ludwiczak, Jacqueline Reinhard, Peter S. Reinach, Aruna Li, Jakub Oronowicz, Aisha Yousf, Vinodh Kakkassery and Stefan Mergler

Int. J. Mol. Sci. 2024, 25(3), 1733; https://doi.org/10.3390/ijms25031733 - 31 Jan 2024

Cited by 2 | Viewed by 1453

Abstract

In childhood, retinoblastoma (RB) is the most common primary tumor in the eye. Long term therapeutic management with etoposide of this life-threatening condition may have diminishing effectiveness since RB cells can develop cytostatic resistance to this drug. To determine whether changes in receptor-mediated [...] Read more.

In childhood, retinoblastoma (RB) is the most common primary tumor in the eye. Long term therapeutic management with etoposide of this life-threatening condition may have diminishing effectiveness since RB cells can develop cytostatic resistance to this drug. To determine whether changes in receptor-mediated control of Ca²⁺ signaling are associated with resistance development, fluorescence calcium imaging, semi-quantitative RT-qPCR analyses, and trypan blue dye exclusion staining patterns are compared in WERI-ETOR (etoposide-insensitive) and WERI-Rb1 (etoposide-sensitive) cells. The cannabinoid receptor agonist 1 (CNR1) WIN55,212-2 (40 µM), or the transient receptor potential melastatin 8 (TRPM8) agonist icilin (40 µM) elicit similar large Ca²⁺ transients in both cell line types. On the other hand, NGF (100 ng/mL) induces larger rises in WERI-ETOR cells than in WERI-Rb1 cells, and its lethality is larger in WERI-Rb1 cells than in WERI-ETOR cells. NGF and WIN55,212-2 induced additive Ca²⁺ transients in both cell types. However, following pretreatment with both NGF and WIN55,212-2, TRPM8 gene expression declines and icilin-induced Ca²⁺ transients are completely blocked only in WERI-ETOR cells. Furthermore, CNR1 gene expression levels are larger in WERI-ETOR cells than those in WERI-Rb1 cells. Therefore, the development of etoposide insensitivity may be associated with rises in CNR1 gene expression, which in turn suppress TRPM8 gene expression through crosstalk. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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27 pages, 4319 KiB

Open AccessArticle

Bidirectional Allosteric Coupling between PIP₂ Binding and the Pore of the Oncochannel TRPV6

by Christina Humer, Tamara Radiskovic, Kata Horváti, Sonja Lindinger, Klaus Groschner, Christoph Romanin and Carmen Höglinger

Int. J. Mol. Sci. 2024, 25(1), 618; https://doi.org/10.3390/ijms25010618 - 3 Jan 2024

Viewed by 1511

Abstract

The epithelial ion channel TRPV6 plays a pivotal role in calcium homeostasis. Channel function is intricately regulated at different stages, involving the lipid phosphatidylinositol-4,5-bisphosphate (PIP₂). Given that dysregulation of TRPV6 is associated with various diseases, including different types of cancer, there [...] Read more.

The epithelial ion channel TRPV6 plays a pivotal role in calcium homeostasis. Channel function is intricately regulated at different stages, involving the lipid phosphatidylinositol-4,5-bisphosphate (PIP₂). Given that dysregulation of TRPV6 is associated with various diseases, including different types of cancer, there is a compelling need for its pharmacological targeting. Structural studies provide insights on how TRPV6 is affected by different inhibitors, with some binding to sites else occupied by lipids. These include the small molecule cis-22a, which, however, also binds to and thereby blocks the pore. By combining calcium imaging, electrophysiology and optogenetics, we identified residues within the pore and the lipid binding site that are relevant for regulation by cis-22a and PIP₂ in a bidirectional manner. Yet, mutation of the cytosolic pore exit reduced inhibition by cis-22a but preserved sensitivity to PIP₂ depletion. Our data underscore allosteric communication between the lipid binding site and the pore and vice versa for most sites along the pore. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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29 pages, 14818 KiB

Open AccessArticle

Cold-Temperature Coding with Bursting and Spiking Based on TRP Channel Dynamics in Drosophila Larva Sensory Neurons

by Natalia Maksymchuk, Akira Sakurai, Daniel N. Cox and Gennady S. Cymbalyuk

Int. J. Mol. Sci. 2023, 24(19), 14638; https://doi.org/10.3390/ijms241914638 - 27 Sep 2023

Viewed by 1426

Abstract

Temperature sensation involves thermosensitive TRP (thermoTRP) and non-TRP channels. Drosophila larval Class III (CIII) neurons serve as the primary cold nociceptors and express a suite of thermoTRP channels implicated in noxious cold sensation. How CIII neurons code temperature remains unclear. We combined computational [...] Read more.

Temperature sensation involves thermosensitive TRP (thermoTRP) and non-TRP channels. Drosophila larval Class III (CIII) neurons serve as the primary cold nociceptors and express a suite of thermoTRP channels implicated in noxious cold sensation. How CIII neurons code temperature remains unclear. We combined computational and electrophysiological methods to address this question. In electrophysiological experiments, we identified two basic cold-evoked patterns of CIII neurons: bursting and spiking. In response to a fast temperature drop to noxious cold, CIII neurons distinctly mark different phases of the stimulus. Bursts frequently occurred along with the fast temperature drop, forming a peak in the spiking rate and likely coding the high rate of the temperature change. Single spikes dominated at a steady temperature and exhibited frequency adaptation following the peak. When temperature decreased slowly to the same value, mainly spiking activity was observed, with bursts occurring sporadically throughout the stimulation. The spike and the burst frequencies positively correlated with the rate of the temperature drop. Using a computational model, we explain the distinction in the occurrence of the two CIII cold-evoked patterns bursting and spiking using the dynamics of a thermoTRP current. A two-parameter activity map (Temperature, constant TRP current conductance) marks parameters that support silent, spiking, and bursting regimes. Projecting on the map the instantaneous TRP conductance, governed by activation and inactivation processes, reflects temperature coding responses as a path across silent, spiking, or bursting domains on the map. The map sheds light on how various parameter sets for TRP kinetics represent various types of cold-evoked responses. Together, our results indicate that bursting detects the high rate of temperature change, whereas tonic spiking could reflect both the rate of change and magnitude of steady cold temperature. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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9 pages, 1956 KiB

Open AccessArticle

Canonical Transient Receptor Potential Channel 3 Contributes to Cerebral Blood Flow Changes Associated with Cortical Spreading Depression in Mice

by Fang Zheng

Int. J. Mol. Sci. 2023, 24(16), 12611; https://doi.org/10.3390/ijms241612611 - 9 Aug 2023

Viewed by 1261

Abstract

Cortical spreading depression is a pathophysiological event shared in migraines, strokes, traumatic brain injuries, and epilepsy. It is associated with complex hemodynamic responses, which, in turn, contribute to neurological problems. In this study, we investigated the role of canonical transient receptor potential channel [...] Read more.

Cortical spreading depression is a pathophysiological event shared in migraines, strokes, traumatic brain injuries, and epilepsy. It is associated with complex hemodynamic responses, which, in turn, contribute to neurological problems. In this study, we investigated the role of canonical transient receptor potential channel 3 (TRPC3) in the hemodynamic responses elicited by cortical spreading depression. Cerebral blood flow was monitored using laser speckle contrast imaging, and cortical spreading depression was triggered using three well-established experimental approaches in mice. A comparison of TRPC3 knockout mice to controls revealed that the genetic ablation of TRPC3 expression significantly altered the hemodynamic responses elicited using cortical spreading depression and promoted hyperemia consistently. Our results indicate that TRPC3 contributes to hemodynamic responses associated with cortical spreading depression and could be a novel therapeutic target for a host of neurological disorders. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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Review

Jump to: Research

19 pages, 1022 KiB

Open AccessReview

Update on the Role of β2AR and TRPV1 in Respiratory Diseases

by Sara Manti, Antonella Gambadauro, Francesca Galletta, Paolo Ruggeri and Giovanni Piedimonte

Int. J. Mol. Sci. 2024, 25(19), 10234; https://doi.org/10.3390/ijms251910234 - 24 Sep 2024

Viewed by 1244

Abstract

Respiratory diseases (RDs) constitute a common public health problem both in industrialized and developing countries. The comprehension of the pathophysiological mechanisms underlying these conditions and the development of new therapeutic strategies are critical for improving the quality of life of affected patients. β2-adrenergic [...] Read more.

Respiratory diseases (RDs) constitute a common public health problem both in industrialized and developing countries. The comprehension of the pathophysiological mechanisms underlying these conditions and the development of new therapeutic strategies are critical for improving the quality of life of affected patients. β2-adrenergic receptor (β2AR) and transient receptor potential vanilloid 1 (TRPV1) are both involved in physiological responses in the airways. β2AR is implicated in bronchodilation, mucociliary clearance, and anti-inflammatory effects, while TRPV1 is involved in the mediation of pain and cough reflexes. In RDs, such as respiratory infections, asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, the concentration and expression of these receptors can be altered, leading to significant consequences. In this review, we provided an update on the literature about the role of β2AR and TRPV1 in these conditions. We reported how the diminished or defective expression of β2AR during viral infections or prolonged therapy with β2-agonists can increase the severity of these pathologies and impact the prognosis. Conversely, the role of TRPV1 was pivotal in neuroinflammation, and its modulation could lead to innovative treatment strategies in specific patients. We indicate future perspectives and potential personalized treatments in RDs through a comprehensive analysis of the roles of these receptors in the physiological and pathological mechanisms of these pathologies. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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19 pages, 4650 KiB

Open AccessReview

TRPA1-Related Diseases and Applications of Nanotherapy

by Dongki Yang

Int. J. Mol. Sci. 2024, 25(17), 9234; https://doi.org/10.3390/ijms25179234 - 26 Aug 2024

Viewed by 850

Abstract

Transient receptor potential (TRP) channels, first identified in Drosophila in 1969, are multifunctional ion channels expressed in various cell types. Structurally, TRP channels consist of six membrane segments and are classified into seven subfamilies. Transient receptor potential ankyrin 1 (TRPA1), the first member [...] Read more.

Transient receptor potential (TRP) channels, first identified in Drosophila in 1969, are multifunctional ion channels expressed in various cell types. Structurally, TRP channels consist of six membrane segments and are classified into seven subfamilies. Transient receptor potential ankyrin 1 (TRPA1), the first member of the TRPA family, is a calcium ion affinity non-selective cation channel involved in sensory transduction and responds to odors, tastes, and chemicals. It also regulates temperature and responses to stimuli. Recent studies have linked TRPA1 to several disorders, including chronic pain, inflammatory diseases, allergies, and respiratory problems, owing to its activation by environmental toxins. Mutations in TRPA1 can affect the sensory nerves and microvasculature, potentially causing nerve pain and vascular problems. Understanding the function of TRPA1 is important for the development of treatments for these diseases. Recent developments in nanomedicines that target various ion channels, including TRPA1, have had a significant impact on disease treatment, providing innovative alternatives to traditional disease treatments by overcoming various adverse effects. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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16 pages, 2350 KiB

Open AccessReview

TRPA1, TRPV1, and Caffeine: Pain and Analgesia

by Elizabeth A. Puthumana, Luna Muhamad, Lexi A. Young and Xiang-Ping Chu

Int. J. Mol. Sci. 2024, 25(14), 7903; https://doi.org/10.3390/ijms25147903 - 19 Jul 2024

Viewed by 3122

Abstract

Caffeine (1,3,7-trimethylxanthine) is a naturally occurring methylxanthine that acts as a potent central nervous system stimulant found in more than 60 different plants and fruits. Although caffeinated beverages are widely and casually consumed, the application of caffeine beyond dietary levels as pharmacologic therapy [...] Read more.

Caffeine (1,3,7-trimethylxanthine) is a naturally occurring methylxanthine that acts as a potent central nervous system stimulant found in more than 60 different plants and fruits. Although caffeinated beverages are widely and casually consumed, the application of caffeine beyond dietary levels as pharmacologic therapy has been recognized since the beginning of its recorded use. The analgesic and vasoactive properties of caffeine are well known, but the extent of their molecular basis remains an area of active research. There is existing evidence in the literature as to caffeine’s effect on TRP channels, the role of caffeine in pain management and analgesia, as well as the role of TRP in pain and analgesia; however, there has yet to be a review focused on the interaction between caffeine and TRP channels. Although the influence of caffeine on TRP has been demonstrated in the lab and in animal models, there is a scarcity of data collected on a large scale as to the clinical utility of caffeine as a regulator of TRP. This review aims to prompt further molecular research to elucidate the specific ligand–host interaction between caffeine and TRP by validating caffeine as a regulator of transient receptor potential (TRP) channels—focusing on the transient receptor potential vanilloid 1 (TRPV1) receptor and transient receptor potential ankyrin 1 (TRPA1) receptor subtypes—and its application in areas of pain. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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14 pages, 1263 KiB

Open AccessReview

Impact of TRP Channels on Extracellular Matrix Remodeling: Focus on TRPV4 and Collagen

by Qin Wang, Chenfan Ji, Patricio Smith and Christopher A. McCulloch

Int. J. Mol. Sci. 2024, 25(7), 3566; https://doi.org/10.3390/ijms25073566 - 22 Mar 2024

Cited by 2 | Viewed by 1590

Abstract

Disturbed remodeling of the extracellular matrix (ECM) is frequently observed in several high-prevalence pathologies that include fibrotic diseases of organs such as the heart, lung, periodontium, liver, and the stiffening of the ECM surrounding invasive cancers. In many of these lesions, matrix remodeling [...] Read more.

Disturbed remodeling of the extracellular matrix (ECM) is frequently observed in several high-prevalence pathologies that include fibrotic diseases of organs such as the heart, lung, periodontium, liver, and the stiffening of the ECM surrounding invasive cancers. In many of these lesions, matrix remodeling mediated by fibroblasts is dysregulated, in part by alterations to the regulatory and effector systems that synthesize and degrade collagen, and by alterations to the functions of the integrin-based adhesions that normally mediate mechanical remodeling of collagen fibrils. Cell-matrix adhesions containing collagen-binding integrins are enriched with regulatory and effector systems that initiate localized remodeling of pericellular collagen fibrils to maintain ECM homeostasis. A large cadre of regulatory molecules is enriched in cell-matrix adhesions that affect ECM remodeling through synthesis, degradation, and contraction of collagen fibrils. One of these regulatory molecules is Transient Receptor Potential Vanilloid-type 4 (TRPV4), a mechanically sensitive, Ca²⁺-permeable plasma membrane channel that regulates collagen remodeling. The gating of Ca²⁺ across the plasma membrane by TRPV4 and the consequent generation of intracellular Ca²⁺ signals affect several processes that determine the structural and mechanical properties of collagen-rich ECM. These processes include the synthesis of new collagen fibrils, tractional remodeling by contractile forces, and collagenolysis. While the specific mechanisms by which TRPV4 contributes to matrix remodeling are not well-defined, it is known that TRPV4 is activated by mechanical forces transmitted through collagen adhesion receptors. Here, we consider how TRPV4 expression and function contribute to physiological and pathological collagen remodeling and are associated with collagen adhesions. Over the long-term, an improved understanding of how TRPV4 regulates collagen remodeling could pave the way for new approaches to manage fibrotic lesions. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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30 pages, 23872 KiB

Open AccessReview

Role of TRP Channels in Metabolism-Related Diseases

by Fengming Wu, Siyuan Bu and Hongmei Wang

Int. J. Mol. Sci. 2024, 25(2), 692; https://doi.org/10.3390/ijms25020692 - 5 Jan 2024

Cited by 2 | Viewed by 2470

Abstract

Metabolic syndrome (MetS), with its high prevalence and significant impact on cardiovascular disease, poses a substantial threat to human health. The early identification of pathological abnormalities related to MetS and prevention of the risk of associated diseases is of paramount importance. Transient Receptor [...] Read more.

Metabolic syndrome (MetS), with its high prevalence and significant impact on cardiovascular disease, poses a substantial threat to human health. The early identification of pathological abnormalities related to MetS and prevention of the risk of associated diseases is of paramount importance. Transient Receptor Potential (TRP) channels, a type of nonselective cation channel, are expressed in a variety of tissues and have been implicated in the onset and progression of numerous metabolism-related diseases. This study aims to review and discuss the expression and function of TRP channels in metabolism-related tissues and blood vessels, and to elucidate the interactions and mechanisms between TRP channels and metabolism-related diseases. A comprehensive literature search was conducted using keywords such as TRP channels, metabolic syndrome, pancreas, liver, oxidative stress, diabetes, hypertension, and atherosclerosis across various academic databases including PubMed, Google Scholar, Elsevier, Web of Science, and CNKI. Our review of the current research suggests that TRP channels may be involved in the development of metabolism-related diseases by regulating insulin secretion and release, lipid metabolism, vascular functional activity, oxidative stress, and inflammatory response. TRP channels, as nonselective cation channels, play pivotal roles in sensing various intra- and extracellular stimuli and regulating ion homeostasis by osmosis. They present potential new targets for the diagnosis or treatment of metabolism-related diseases. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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21 pages, 1319 KiB

Open AccessReview

Interaction of Calmodulin with TRPM: An Initiator of Channel Modulation

by Kristyna Vydra Bousova, Monika Zouharova, Katerina Jiraskova and Veronika Vetyskova

Int. J. Mol. Sci. 2023, 24(20), 15162; https://doi.org/10.3390/ijms242015162 - 13 Oct 2023

Cited by 1 | Viewed by 1904

Abstract

Transient receptor potential melastatin (TRPM) channels, a subfamily of the TRP superfamily, constitute a diverse group of ion channels involved in mediating crucial cellular processes like calcium homeostasis. These channels exhibit complex regulation, and one of the key regulatory mechanisms involves their interaction [...] Read more.

Transient receptor potential melastatin (TRPM) channels, a subfamily of the TRP superfamily, constitute a diverse group of ion channels involved in mediating crucial cellular processes like calcium homeostasis. These channels exhibit complex regulation, and one of the key regulatory mechanisms involves their interaction with calmodulin (CaM), a cytosol ubiquitous calcium-binding protein. The association between TRPM channels and CaM relies on the presence of specific CaM-binding domains in the channel structure. Upon CaM binding, the channel undergoes direct and/or allosteric structural changes and triggers down- or up-stream signaling pathways. According to current knowledge, ion channel members TRPM2, TRPM3, TRPM4, and TRPM6 are directly modulated by CaM, resulting in their activation or inhibition. This review specifically focuses on the interplay between TRPM channels and CaM and summarizes the current known effects of CaM interactions and modulations on TRPM channels in cellular physiology. Full article

(This article belongs to the Special Issue TRP Channels in Physiology and Pathophysiology 2.0)

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