Cells

Editorial

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8 pages, 230 KiB

Open AccessEditorial

Transient Receptor Potential Canonical Channels in Health and Disease: A 2020 Update

by Priya R. Kirtley, Gagandeep S. Sooch, Fletcher A. White and Alexander G. Obukhov

Cells 2021, 10(3), 496; https://doi.org/10.3390/cells10030496 - 25 Feb 2021

Cited by 2 | Viewed by 2121

Abstract

This 2020 Special Issue “TRPC channels” of Cells was dedicated to commemorating the 25th anniversary of discovery of the Transient Receptor Potential Canonical (TRPC) channel subfamily [...] Full article

(This article belongs to the Special Issue TRPC Channels)

Research

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11 pages, 1902 KiB

Open AccessFeature PaperArticle

Light-Mediated Control over TRPC3-Mediated NFAT Signaling

by Annarita Graziani, Bernadett Bacsa, Denis Krivic, Patrick Wiedner, Sanja Curcic, Rainer Schindl, Oleksandra Tiapko and Klaus Groschner

Cells 2020, 9(3), 556; https://doi.org/10.3390/cells9030556 - 27 Feb 2020

Cited by 4 | Viewed by 3279

Abstract

Canonical transient receptor potential (TRPC) channels were identified as key players in maladaptive remodeling, with nuclear factor of activated T-cells (NFAT) transcription factors serving as downstream targets of TRPC-triggered Ca²⁺ entry in these pathological processes. Strikingly, the reconstitution of TRPC-NFAT signaling by [...] Read more.

Canonical transient receptor potential (TRPC) channels were identified as key players in maladaptive remodeling, with nuclear factor of activated T-cells (NFAT) transcription factors serving as downstream targets of TRPC-triggered Ca²⁺ entry in these pathological processes. Strikingly, the reconstitution of TRPC-NFAT signaling by heterologous expression yielded controversial results. Specifically, nuclear translocation of NFAT1 was found barely responsive to recombinant TRPC3, presumably based on the requirement of certain spatiotemporal signaling features. Here, we report efficient control of NFAT1 nuclear translocation in human embryonic kidney 293 (HEK293) cells by light, using a new photochromic TRPC benzimidazole activator (OptoBI-1) and a TRPC3 mutant with modified activator sensitivity. NFAT1 nuclear translocation was measured along with an all-optical protocol to record local and global Ca²⁺ pattern generated during light-mediated activation/deactivation cycling of TRPC3. Our results unveil the ability of wild-type TRPC3 to produce constitutive NFAT nuclear translocation. Moreover, we demonstrate that TRPC3 mutant that lacks basal activity enables spatiotemporally precise control over NFAT1 activity by photopharmacology. Our results suggest tight linkage between TRPC3 activity and NFAT1 nuclear translocation based on global cellular Ca²⁺ signals. Full article

(This article belongs to the Special Issue TRPC Channels)

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17 pages, 4167 KiB

Open AccessFeature PaperArticle

Transient Receptor Potential Canonical 5-Scramblase Signaling Complex Mediates Neuronal Phosphatidylserine Externalization and Apoptosis

by Jizheng Guo, Jie Li, Lin Xia, Yang Wang, Jinhang Zhu, Juan Du, Yungang Lu, Guodong Liu, Xiaoqiang Yao and Bing Shen

Cells 2020, 9(3), 547; https://doi.org/10.3390/cells9030547 - 26 Feb 2020

Cited by 12 | Viewed by 3959

Abstract

Phospholipid scramblase 1 (PLSCR1), a lipid-binding and Ca²⁺-sensitive protein located on plasma membranes, is critically involved in phosphatidylserine (PS) externalization, an important process in cell apoptosis. Transient receptor potential canonical 5 (TRPC5), is a nonselective Ca²⁺ channel in neurons that [...] Read more.

Phospholipid scramblase 1 (PLSCR1), a lipid-binding and Ca²⁺-sensitive protein located on plasma membranes, is critically involved in phosphatidylserine (PS) externalization, an important process in cell apoptosis. Transient receptor potential canonical 5 (TRPC5), is a nonselective Ca²⁺ channel in neurons that interacts with many downstream molecules, participating in diverse physiological functions including temperature or mechanical sensation. The interaction between TRPC5 and PLSCR1 has never been reported. Here, we showed that PLSCR1 interacts with TRPC5 through their C-termini in HEK293 cells and mouse cortical neurons. Formation of TRPC5-PLSCR1 complex stimulates PS externalization and promotes cell apoptosis in HEK293 cells and mouse cerebral neurons. Furthermore, in vivo studies showed that PS externalization in cortical neurons induced by artificial cerebral ischemia-reperfusion was reduced in TRPC5 knockout mice compared to wild-type mice, and that the percentage of apoptotic neurons was also lower in TRPC5 knockout mice than in wild-type mice. Collectively, the present study suggested that TRPC5-PLSCR1 is a signaling complex mediating PS externalization and apoptosis in neurons and that TRPC5 plays a pathological role in cerebral-ischemia reperfusion injury. Full article

(This article belongs to the Special Issue TRPC Channels)

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16 pages, 2541 KiB

Open AccessArticle

TRPC1 Regulates the Activity of a Voltage-Dependent Nonselective Cation Current in Hippocampal CA1 Neurons

by Frauke Kepura, Eva Braun, Alexander Dietrich and Tim D. Plant

Cells 2020, 9(2), 459; https://doi.org/10.3390/cells9020459 - 18 Feb 2020

Cited by 6 | Viewed by 2763

Abstract

The cation channel subunit TRPC1 is strongly expressed in central neurons including neurons in the CA1 region of the hippocampus where it forms complexes with TRPC4 and TRPC5. To investigate the functional role of TRPC1 in these neurons and in channel function, we [...] Read more.

The cation channel subunit TRPC1 is strongly expressed in central neurons including neurons in the CA1 region of the hippocampus where it forms complexes with TRPC4 and TRPC5. To investigate the functional role of TRPC1 in these neurons and in channel function, we compared current responses to group I metabotropic glutamate receptor (mGluR I) activation and looked for major differences in dendritic morphology in neurons from TRPC1^+/+ and TRPC1^−/− mice. mGluR I stimulation resulted in the activation of a voltage-dependent nonselective cation current in both genotypes. Deletion of TRPC1 resulted in a modification of the shape of the current-voltage relationship, leading to an inward current increase. In current clamp recordings, the percentage of neurons that responded to depolarization in the presence of an mGluR I agonist with a plateau potential was increased in TRPC1^−/− mice. There was also a small increase in the minor population of CA1 neurons that have more than one apical dendrite in TRPC1^−/− mice. We conclude that TRPC1 has an inhibitory effect on receptor-operated nonselective cation channels in hippocampal CA1 neurons probably as a result of heterotetramer formation with other TRPC isoforms, and that TRPC1 deletion has only minor effects on dendritic morphology. Full article

(This article belongs to the Special Issue TRPC Channels)

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20 pages, 1966 KiB

Open AccessArticle

Involvement of TRPC4 and 5 Channels in Persistent Firing in Hippocampal CA1 Pyramidal Cells

by Alberto Arboit, Antonio Reboreda and Motoharu Yoshida

Cells 2020, 9(2), 365; https://doi.org/10.3390/cells9020365 - 5 Feb 2020

Cited by 14 | Viewed by 4127

Abstract

Persistent neural activity has been observed in vivo during working memory tasks, and supports short-term (up to tens of seconds) retention of information. While synaptic and intrinsic cellular mechanisms of persistent firing have been proposed, underlying cellular mechanisms are not yet fully understood. [...] Read more.

Persistent neural activity has been observed in vivo during working memory tasks, and supports short-term (up to tens of seconds) retention of information. While synaptic and intrinsic cellular mechanisms of persistent firing have been proposed, underlying cellular mechanisms are not yet fully understood. In vitro experiments have shown that individual neurons in the hippocampus and other working memory related areas support persistent firing through intrinsic cellular mechanisms that involve the transient receptor potential canonical (TRPC) channels. Recent behavioral studies demonstrating the involvement of TRPC channels on working memory make the hypothesis that TRPC driven persistent firing supports working memory a very attractive one. However, this view has been challenged by recent findings that persistent firing in vitro is unchanged in TRPC knock out (KO) mice. To assess the involvement of TRPC channels further, we tested novel and highly specific TRPC channel blockers in cholinergically induced persistent firing in mice CA1 pyramidal cells for the first time. The application of the TRPC4 blocker ML204, TRPC5 blocker clemizole hydrochloride, and TRPC4 and 5 blocker Pico145, all significantly inhibited persistent firing. In addition, intracellular application of TRPC4 and TRPC5 antibodies significantly reduced persistent firing. Taken together these results indicate that TRPC4 and 5 channels support persistent firing in CA1 pyramidal neurons. Finally, we discuss possible scenarios causing these controversial observations on the role of TRPC channels in persistent firing. Full article

(This article belongs to the Special Issue TRPC Channels)

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21 pages, 3286 KiB

Open AccessArticle

Angiotensin-II-Evoked Ca²⁺ Entry in Murine Cardiac Fibroblasts Does Not Depend on TRPC Channels

by Juan E. Camacho Londoño, André Marx, Axel E. Kraft, Alexander Schürger, Christin Richter, Alexander Dietrich, Peter Lipp, Lutz Birnbaumer and Marc Freichel

Cells 2020, 9(2), 322; https://doi.org/10.3390/cells9020322 - 29 Jan 2020

Cited by 13 | Viewed by 4015

Abstract

TRPC proteins form cation conducting channels regulated by different stimuli and are regulators of the cellular calcium homeostasis. TRPC are expressed in cardiac cells including cardiac fibroblasts (CFs) and have been implicated in the development of pathological cardiac remodeling including fibrosis. Using Ca [...] Read more.

TRPC proteins form cation conducting channels regulated by different stimuli and are regulators of the cellular calcium homeostasis. TRPC are expressed in cardiac cells including cardiac fibroblasts (CFs) and have been implicated in the development of pathological cardiac remodeling including fibrosis. Using Ca²⁺ imaging and several compound TRPC knockout mouse lines we analyzed the involvement of TRPC proteins for the angiotensin II (AngII)-induced changes in Ca²⁺ homeostasis in CFs isolated from adult mice. Using qPCR we detected transcripts of all Trpc genes in CFs; Trpc1, Trpc3 and Trpc4 being the most abundant ones. We show that the AngII-induced Ca²⁺ entry but also Ca²⁺ release from intracellular stores are critically dependent on the density of CFs in culture and are inversely correlated with the expression of the myofibroblast marker α-smooth muscle actin. Our Ca²⁺ measurements depict that the AngII- and thrombin-induced Ca²⁺ transients, and the AngII-induced Ca²⁺ entry and Ca²⁺ release are not affected in CFs isolated from mice lacking all seven TRPC proteins (TRPC-hepta KO) compared to control cells. However, pre-incubation with GSK7975A (10 µM), which sufficiently inhibits CRAC channels in other cells, abolished AngII-induced Ca²⁺ entry. Consequently, we conclude the dispensability of the TRPC channels for the acute neurohumoral Ca²⁺ signaling evoked by AngII in isolated CFs and suggest the contribution of members of the Orai channel family as molecular constituents responsible for this pathophysiologically important Ca²⁺ entry pathway. Full article

(This article belongs to the Special Issue TRPC Channels)

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16 pages, 3560 KiB

Open AccessFeature PaperArticle

Direct Activation of TRPC3 Channels by the Antimalarial Agent Artemisinin

by Nicole Urban and Michael Schaefer

Cells 2020, 9(1), 202; https://doi.org/10.3390/cells9010202 - 14 Jan 2020

Cited by 16 | Viewed by 4255

Abstract

(1) Background: Members of the TRPC3/TRPC6/TRPC7 subfamily of canonical transient receptor potential (TRP) channels share an amino acid similarity of more than 80% and can form heteromeric channel complexes. They are directly gated by diacylglycerols in a protein kinase C-independent manner. To assess [...] Read more.

(1) Background: Members of the TRPC3/TRPC6/TRPC7 subfamily of canonical transient receptor potential (TRP) channels share an amino acid similarity of more than 80% and can form heteromeric channel complexes. They are directly gated by diacylglycerols in a protein kinase C-independent manner. To assess TRPC3 channel functions without concomitant protein kinase C activation, direct activators are highly desirable. (2) Methods: By screening 2000 bioactive compounds in a Ca²⁺ influx assay, we identified artemisinin as a TRPC3 activator. Validation and characterization of the hit was performed by applying fluorometric Ca²⁺ influx assays and electrophysiological patch-clamp experiments in heterologously or endogenously TRPC3-expressing cells. (3) Results: Artemisinin elicited Ca²⁺ entry through TRPC3 or heteromeric TRPC3:TRPC6 channels, but did not or only weakly activated TRPC6 and TRPC7. Electrophysiological recordings confirmed the reversible and repeatable TRPC3 activation by artemisinin that was inhibited by established TRPC3 channel blockers. Rectification properties and reversal potentials were similar to those observed after stimulation with a diacylglycerol mimic, indicating that artemisinin induces a similar active state as the physiological activator. In rat pheochromocytoma PC12 cells that endogenously express TRPC3, artemisinin induced a Ca²⁺ influx and TRPC3-like currents. (4) Conclusions: Our findings identify artemisinin as a new biologically active entity to activate recombinant or native TRPC3-bearing channel complexes in a membrane-confined fashion. Full article

(This article belongs to the Special Issue TRPC Channels)

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14 pages, 2126 KiB

Open AccessCommunication

Specific Upregulation of TRPC1 and TRPC5 Channels by Mineralocorticoid Pathway in Adult Rat Ventricular Cardiomyocytes

by Fiona Bartoli, Soraya Moradi Bachiller, Fabrice Antigny, Kaveen Bedouet, Pascale Gerbaud, Jessica Sabourin and Jean-Pierre Benitah

Cells 2020, 9(1), 47; https://doi.org/10.3390/cells9010047 - 23 Dec 2019

Cited by 11 | Viewed by 3819

Abstract

Whereas cardiac TRPC (transient receptor potential canonical) channels and the associated store-operated Ca²⁺ entry (SOCE) are abnormally elevated during cardiac hypertrophy and heart failure, the mechanism of this upregulation is not fully elucidated but might be related to the activation of the [...] Read more.

Whereas cardiac TRPC (transient receptor potential canonical) channels and the associated store-operated Ca²⁺ entry (SOCE) are abnormally elevated during cardiac hypertrophy and heart failure, the mechanism of this upregulation is not fully elucidated but might be related to the activation of the mineralocorticoid pathway. Using a combination of biochemical, Ca²⁺ imaging, and electrophysiological techniques, we determined the effect of 24-h aldosterone treatment on the TRPCs/Orai-dependent SOCE in adult rat ventricular cardiomyocytes (ARVMs). The 24-h aldosterone treatment (from 100 nM to 1 µM) enhanced depletion-induced Ca²⁺ entry in ARVMs, as assessed by a faster reduction of Fura-2 fluorescence decay upon the addition of Mn²⁺ and increased Fluo-4/AM fluorescence following Ca²⁺ store depletion. These effects were prevented by co-treatment with a specific mineralocorticoid receptor (MR) antagonist, RU-28318, and they are associated with the enhanced depletion-induced N-[4-[3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-4-methyl-1,2,3-thiadiazole-5-carboxamide (BTP2)-sensitive macroscopic current recorded by patch-clamp experiments. Molecular screening by qRT-PCR and Western blot showed a specific upregulation of TRPC1, TRPC5, and STIM1 expression at the messenger RNA (mRNA) and protein levels upon 24-h aldosterone treatment of ARVMs, corroborated by immunostaining. Our study provides evidence that the mineralocorticoid pathway specifically promotes TRPC1/TRPC5-mediated SOCE in adult rat cardiomyocytes. Full article

(This article belongs to the Special Issue TRPC Channels)

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Review

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48 pages, 8420 KiB

Open AccessReview

Transient Receptor Potential Canonical (TRPC) Channels: Then and Now

by Xingjuan Chen, Gagandeep Sooch, Isaac S. Demaree, Fletcher A. White and Alexander G. Obukhov

Cells 2020, 9(9), 1983; https://doi.org/10.3390/cells9091983 - 28 Aug 2020

Cited by 92 | Viewed by 8618

Abstract

Twenty-five years ago, the first mammalian Transient Receptor Potential Canonical (TRPC) channel was cloned, opening the vast horizon of the TRPC field. Today, we know that there are seven TRPC channels (TRPC1–7). TRPCs exhibit the highest protein sequence similarity to the Drosophila melanogaster [...] Read more.

Twenty-five years ago, the first mammalian Transient Receptor Potential Canonical (TRPC) channel was cloned, opening the vast horizon of the TRPC field. Today, we know that there are seven TRPC channels (TRPC1–7). TRPCs exhibit the highest protein sequence similarity to the Drosophila melanogaster TRP channels. Similar to Drosophila TRPs, TRPCs are localized to the plasma membrane and are activated in a G-protein-coupled receptor-phospholipase C-dependent manner. TRPCs may also be stimulated in a store-operated manner, via receptor tyrosine kinases, or by lysophospholipids, hypoosmotic solutions, and mechanical stimuli. Activated TRPCs allow the influx of Ca²⁺ and monovalent alkali cations into the cytosol of cells, leading to cell depolarization and rising intracellular Ca²⁺ concentration. TRPCs are involved in the continually growing number of cell functions. Furthermore, mutations in the TRPC6 gene are associated with hereditary diseases, such as focal segmental glomerulosclerosis. The most important recent breakthrough in TRPC research was the solving of cryo-EM structures of TRPC3, TRPC4, TRPC5, and TRPC6. These structural data shed light on the molecular mechanisms underlying TRPCs’ functional properties and propelled the development of new modulators of the channels. This review provides a historical overview of the major advances in the TRPC field focusing on the role of gene knockouts and pharmacological tools. Full article

(This article belongs to the Special Issue TRPC Channels)

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19 pages, 1220 KiB

Open AccessReview

TRPCs: Influential Mediators in Skeletal Muscle

by Jun Hee Choi, Seung Yeon Jeong, Mi Ri Oh, Paul D. Allen and Eun Hui Lee

Cells 2020, 9(4), 850; https://doi.org/10.3390/cells9040850 - 1 Apr 2020

Cited by 25 | Viewed by 5370

Abstract

Ca²⁺ itself or Ca²⁺-dependent signaling pathways play fundamental roles in various cellular processes from cell growth to death. The most representative example can be found in skeletal muscle cells where a well-timed and adequate supply of Ca²⁺ is required [...] Read more.

Ca²⁺ itself or Ca²⁺-dependent signaling pathways play fundamental roles in various cellular processes from cell growth to death. The most representative example can be found in skeletal muscle cells where a well-timed and adequate supply of Ca²⁺ is required for coordinated Ca²⁺-dependent skeletal muscle functions, such as the interactions of contractile proteins during contraction. Intracellular Ca²⁺ movements between the cytosol and sarcoplasmic reticulum (SR) are strictly regulated to maintain the appropriate Ca²⁺ supply in skeletal muscle cells. Added to intracellular Ca²⁺ movements, the contribution of extracellular Ca²⁺ entry to skeletal muscle functions and its significance have been continuously studied since the early 1990s. Here, studies on the roles of channel proteins that mediate extracellular Ca²⁺ entry into skeletal muscle cells using skeletal myoblasts, myotubes, fibers, tissue, or skeletal muscle-originated cell lines are reviewed with special attention to the proposed functions of transient receptor potential canonical proteins (TRPCs) as store-operated Ca²⁺ entry (SOCE) channels under normal conditions and the potential abnormal properties of TRPCs in muscle diseases such as Duchenne muscular dystrophy (DMD). Full article

(This article belongs to the Special Issue TRPC Channels)

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22 pages, 725 KiB

Open AccessFeature PaperReview

Molecular Regulations and Functions of the Transient Receptor Potential Channels of the Islets of Langerhans and Insulinoma Cells

by Md. Shahidul Islam

Cells 2020, 9(3), 685; https://doi.org/10.3390/cells9030685 - 11 Mar 2020

Cited by 23 | Viewed by 5212

Abstract

Insulin secretion from the β-cells of the islets of Langerhans is triggered mainly by nutrients such as glucose, and incretin hormones such as glucagon-like peptide-1 (GLP-1). The mechanisms of the stimulus-secretion coupling involve the participation of the key enzymes that metabolize the nutrients, [...] Read more.

Insulin secretion from the β-cells of the islets of Langerhans is triggered mainly by nutrients such as glucose, and incretin hormones such as glucagon-like peptide-1 (GLP-1). The mechanisms of the stimulus-secretion coupling involve the participation of the key enzymes that metabolize the nutrients, and numerous ion channels that mediate the electrical activity. Several members of the transient receptor potential (TRP) channels participate in the processes that mediate the electrical activities and Ca²⁺ oscillations in these cells. Human β-cells express TRPC1, TRPM2, TRPM3, TRPM4, TRPM7, TRPP1, TRPML1, and TRPML3 channels. Some of these channels have been reported to mediate background depolarizing currents, store-operated Ca²⁺ entry (SOCE), electrical activity, Ca²⁺ oscillations, gene transcription, cell-death, and insulin secretion in response to stimulation by glucose and GLP1. Different channels of the TRP family are regulated by one or more of the following mechanisms: activation of G protein-coupled receptors, the filling state of the endoplasmic reticulum Ca²⁺ store, heat, oxidative stress, or some second messengers. This review briefly compiles our current knowledge about the molecular mechanisms of regulations, and functions of the TRP channels in the β-cells, the α-cells, and some insulinoma cell lines. Full article

(This article belongs to the Special Issue TRPC Channels)

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16 pages, 890 KiB

Open AccessReview

TRPC Channels in Cardiac Plasticity

by Takuro Numaga-Tomita and Motohiro Nishida

Cells 2020, 9(2), 454; https://doi.org/10.3390/cells9020454 - 17 Feb 2020

Cited by 16 | Viewed by 4666

Abstract

The heart flexibly changes its structure in response to changing environments and oxygen/nutrition demands of the body. Increased and decreased mechanical loading induces hypertrophy and atrophy of cardiomyocytes, respectively. In physiological conditions, these structural changes of the heart are reversible. However, chronic stresses [...] Read more.

The heart flexibly changes its structure in response to changing environments and oxygen/nutrition demands of the body. Increased and decreased mechanical loading induces hypertrophy and atrophy of cardiomyocytes, respectively. In physiological conditions, these structural changes of the heart are reversible. However, chronic stresses such as hypertension or cancer cachexia cause irreversible remodeling of the heart, leading to heart failure. Accumulating evidence indicates that calcium dyshomeostasis and aberrant reactive oxygen species production cause pathological heart remodeling. Canonical transient receptor potential (TRPC) is a nonselective cation channel subfamily whose multimodal activation or modulation of channel activity play important roles in a plethora of cellular physiology. Roles of TRPC channels in cardiac physiology have been reported in pathological cardiac remodeling. In this review, we summarize recent findings regarding the importance of TRPC channels in flexible cardiac remodeling (i.e., cardiac plasticity) in response to environmental stresses and discuss questions that should be addressed in the near future. Full article

(This article belongs to the Special Issue TRPC Channels)

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13 pages, 1319 KiB

Open AccessReview

The Role of TRPC1 in Modulating Cancer Progression

by Osama M Elzamzamy, Reinhold Penner and Lori A Hazlehurst

Cells 2020, 9(2), 388; https://doi.org/10.3390/cells9020388 - 7 Feb 2020

Cited by 52 | Viewed by 6371

Abstract

Calcium ions (Ca²⁺) play an important role as second messengers in regulating a plethora of physiological and pathological processes, including the progression of cancer. Several selective and non-selective Ca²⁺-permeable ion channels are implicated in mediating Ca²⁺ signaling in [...] Read more.

Calcium ions (Ca²⁺) play an important role as second messengers in regulating a plethora of physiological and pathological processes, including the progression of cancer. Several selective and non-selective Ca²⁺-permeable ion channels are implicated in mediating Ca²⁺ signaling in cancer cells. In this review, we are focusing on TRPC1, a member of the TRP protein superfamily and a potential modulator of store-operated Ca²⁺ entry (SOCE) pathways. While TRPC1 is ubiquitously expressed in most tissues, its dysregulated activity may contribute to the hallmarks of various types of cancers, including breast cancer, pancreatic cancer, glioblastoma multiforme, lung cancer, hepatic cancer, multiple myeloma, and thyroid cancer. A range of pharmacological and genetic tools have been developed to address the functional role of TRPC1 in cancer. Interestingly, the unique role of TRPC1 has elevated this channel as a promising target for modulation both in terms of pharmacological inhibition leading to suppression of tumor growth and metastasis, as well as for agonistic strategies eliciting Ca²⁺ overload and cell death in aggressive metastatic tumor cells. Full article

(This article belongs to the Special Issue TRPC Channels)

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13 pages, 388 KiB

Open AccessReview

Insights into Activation Mechanisms of Store-Operated TRPC1 Channels in Vascular Smooth Muscle

by Miguel A. S. Martín-Aragón Baudel, Jian Shi, William A. Large and Anthony P. Albert

Cells 2020, 9(1), 179; https://doi.org/10.3390/cells9010179 - 10 Jan 2020

Cited by 12 | Viewed by 3961

Abstract

In vascular smooth muscle cells (VMSCs), the stimulation of store-operated channels (SOCs) mediate Ca²⁺ influx pathways which regulate important cellular functions including contraction, proliferation, migration, and growth that are associated with the development of vascular diseases. It is therefore important that we [...] Read more.

In vascular smooth muscle cells (VMSCs), the stimulation of store-operated channels (SOCs) mediate Ca²⁺ influx pathways which regulate important cellular functions including contraction, proliferation, migration, and growth that are associated with the development of vascular diseases. It is therefore important that we understand the biophysical, molecular composition, activation pathways, and physiological significance of SOCs in VSMCs as these maybe future therapeutic targets for conditions such as hypertension and atherosclerosis. Archetypal SOCs called calcium release-activated channels (CRACs) are composed of Orai1 proteins and are stimulated by the endo/sarcoplasmic reticulum Ca²⁺ sensor stromal interaction molecule 1 (STIM1) following store depletion. In contrast, this review focuses on proposals that canonical transient receptor potential (TRPC) channels composed of a heteromeric TRPC1/C5 molecular template, with TRPC1 conferring activation by store depletion, mediate SOCs in native contractile VSMCs. In particular, it summarizes our recent findings which describe a novel activation pathway of these TRPC1-based SOCs, in which protein kinase C (PKC)-dependent TRPC1 phosphorylation and phosphatidylinositol 4,5-bisphosphate (PIP₂) are obligatory for channel opening. This PKC- and PIP₂-mediated gating mechanism is regulated by the PIP₂-binding protein myristoylated alanine-rich C kinase (MARCKS) and is coupled to store depletion by TRPC1-STIM1 interactions which induce Gq/PLCβ1 activity. Interestingly, the biophysical properties and activation mechanisms of TRPC1-based SOCs in native contractile VSMCs are unlikely to involve Orai1. Full article

(This article belongs to the Special Issue TRPC Channels)

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16 pages, 546 KiB

Open AccessReview

TRPC Channels: Dysregulation and Ca²⁺ Mishandling in Ischemic Heart Disease

by Débora Falcón, Isabel Galeano-Otero, Marta Martín-Bórnez, María Fernández-Velasco, Isabel Gallardo-Castillo, Juan A. Rosado, Antonio Ordóñez and Tarik Smani

Cells 2020, 9(1), 173; https://doi.org/10.3390/cells9010173 - 10 Jan 2020

Cited by 19 | Viewed by 5050

Abstract

Transient receptor potential canonical (TRPC) channels are ubiquitously expressed in excitable and non-excitable cardiac cells where they sense and respond to a wide variety of physical and chemical stimuli. As other TRP channels, TRPC channels may form homo or heterotetrameric ion channels, and [...] Read more.

Transient receptor potential canonical (TRPC) channels are ubiquitously expressed in excitable and non-excitable cardiac cells where they sense and respond to a wide variety of physical and chemical stimuli. As other TRP channels, TRPC channels may form homo or heterotetrameric ion channels, and they can associate with other membrane receptors and ion channels to regulate intracellular calcium concentration. Dysfunctions of TRPC channels are involved in many types of cardiovascular diseases. Significant increase in the expression of different TRPC isoforms was observed in different animal models of heart infarcts and in vitro experimental models of ischemia and reperfusion. TRPC channel-mediated increase of the intracellular Ca²⁺ concentration seems to be required for the activation of the signaling pathway that plays minor roles in the healthy heart, but they are more relevant for cardiac responses to ischemia, such as the activation of different factors of transcription and cardiac hypertrophy, fibrosis, and angiogenesis. In this review, we highlight the current knowledge regarding TRPC implication in different cellular processes related to ischemia and reperfusion and to heart infarction. Full article

(This article belongs to the Special Issue TRPC Channels)

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37 pages, 3962 KiB

Open AccessReview

Post-Translational Modification and Natural Mutation of TRPC Channels

by Xianji Liu, Xiaoqiang Yao and Suk Ying Tsang

Cells 2020, 9(1), 135; https://doi.org/10.3390/cells9010135 - 7 Jan 2020

Cited by 16 | Viewed by 6252

Abstract

Transient Receptor Potential Canonical (TRPC) channels are homologues of Drosophila TRP channel first cloned in mammalian cells. TRPC family consists of seven members which are nonselective cation channels with a high Ca²⁺ permeability and are activated by a wide spectrum of stimuli. [...] Read more.

Transient Receptor Potential Canonical (TRPC) channels are homologues of Drosophila TRP channel first cloned in mammalian cells. TRPC family consists of seven members which are nonselective cation channels with a high Ca²⁺ permeability and are activated by a wide spectrum of stimuli. These channels are ubiquitously expressed in different tissues and organs in mammals and exert a variety of physiological functions. Post-translational modifications (PTMs) including phosphorylation, N-glycosylation, disulfide bond formation, ubiquitination, S-nitrosylation, S-glutathionylation, and acetylation play important roles in the modulation of channel gating, subcellular trafficking, protein-protein interaction, recycling, and protein architecture. PTMs also contribute to the polymodal activation of TRPCs and their subtle regulation in diverse physiological contexts and in pathological situations. Owing to their roles in the motor coordination and regulation of kidney podocyte structure, mutations of TRPCs have been implicated in diseases like cerebellar ataxia (moonwalker mice) and focal and segmental glomerulosclerosis (FSGS). The aim of this review is to comprehensively integrate all reported PTMs of TRPCs, to discuss their physiological/pathophysiological roles if available, and to summarize diseases linked to the natural mutations of TRPCs. Full article

(This article belongs to the Special Issue TRPC Channels)

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13 pages, 2115 KiB

Open AccessReview

TRPC Channels in the SOCE Scenario

by Jose J. Lopez, Isaac Jardin, Jose Sanchez-Collado, Ginés M. Salido, Tarik Smani and Juan A. Rosado

Cells 2020, 9(1), 126; https://doi.org/10.3390/cells9010126 - 5 Jan 2020

Cited by 63 | Viewed by 6098

Abstract

Transient receptor potential (TRP) proteins form non-selective Ca²⁺ permeable channels that contribute to the modulation of a number of physiological functions in a variety of cell types. Since the identification of TRP proteins in Drosophila, it is well known that these [...] Read more.

Transient receptor potential (TRP) proteins form non-selective Ca²⁺ permeable channels that contribute to the modulation of a number of physiological functions in a variety of cell types. Since the identification of TRP proteins in Drosophila, it is well known that these channels are activated by stimuli that induce PIP₂ hydrolysis. The canonical TRP (TRPC) channels have long been suggested to be constituents of the store-operated Ca²⁺ (SOC) channels; however, none of the TRPC channels generate Ca²⁺ currents that resemble I_CRAC. STIM1 and Orai1 have been identified as the components of the Ca²⁺ release-activated Ca²⁺ (CRAC) channels and there is a body of evidence supporting that STIM1 is able to gate Orai1 and TRPC1 in order to mediate non-selective cation currents named I_SOC. STIM1 has been found to interact to and activate Orai1 and TRPC1 by different mechanisms and the involvement of TRPC1 in store-operated Ca²⁺ entry requires both STIM1 and Orai1. In addition to the participation of TRPC1 in the I_SOC currents, TRPC1 and other TRPC proteins might play a relevant role modulating Orai1 channel function. This review summarizes the functional role of TRPC channels in the STIM1–Orai1 scenario. Full article

(This article belongs to the Special Issue TRPC Channels)

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24 pages, 5820 KiB

Open AccessReview

Structure–Function Relationship and Physiological Roles of Transient Receptor Potential Canonical (TRPC) 4 and 5 Channels

by Jinsung Kim, Juyeon Ko, Chansik Hong and Insuk So

Cells 2020, 9(1), 73; https://doi.org/10.3390/cells9010073 - 27 Dec 2019

Cited by 16 | Viewed by 4961

Abstract

The study of the structure–function relationship of ion channels has been one of the most challenging goals in contemporary physiology. Revelation of the three-dimensional (3D) structure of ion channels has facilitated our understanding of many of the submolecular mechanisms inside ion channels, such [...] Read more.

The study of the structure–function relationship of ion channels has been one of the most challenging goals in contemporary physiology. Revelation of the three-dimensional (3D) structure of ion channels has facilitated our understanding of many of the submolecular mechanisms inside ion channels, such as selective permeability, voltage dependency, agonist binding, and inter-subunit multimerization. Identifying the structure–function relationship of the ion channels is clinically important as well since only such knowledge can imbue potential therapeutics with practical possibilities. In a sense, recent advances in the understanding of the structure–relationship of transient receptor potential canonical (TRPC) channels look promising since human TRPC channels are calcium-permeable, non-selective cation channels expressed in many tissues such as the gastrointestinal (GI) tract, kidney, heart, vasculature, and brain. TRPC channels are known to regulate GI contractility and motility, pulmonary hypertension, right ventricular hypertrophy, podocyte injury, seizure, fear, anxiety-like behavior, and many others. In this article, we tried to elaborate recent findings of Cryo-EM (cryogenic-electron microscopy) based structural information of TRPC 4 and 5 channels and domain-specific functions of the channel, such as G-protein mediated activation mechanism, extracellular modification of the channel, homo/hetero-tetramerization, and pharmacological gating mechanisms. Full article

(This article belongs to the Special Issue TRPC Channels)

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Open AccessReview

TRPC Channels in Proteinuric Kidney Diseases

by Gentzon Hall, Liming Wang and Robert F. Spurney

Cells 2020, 9(1), 44; https://doi.org/10.3390/cells9010044 - 23 Dec 2019

Cited by 45 | Viewed by 7827

Abstract

Over a decade ago, mutations in the gene encoding TRPC6 (transient receptor potential cation channel, subfamily C, member 6) were linked to development of familial forms of nephrosis. Since this discovery, TRPC6 has been implicated in the pathophysiology of non-genetic forms of kidney [...] Read more.

Over a decade ago, mutations in the gene encoding TRPC6 (transient receptor potential cation channel, subfamily C, member 6) were linked to development of familial forms of nephrosis. Since this discovery, TRPC6 has been implicated in the pathophysiology of non-genetic forms of kidney disease including focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, immune-mediated kidney diseases, and renal fibrosis. On the basis of these findings, TRPC6 has become an important target for the development of therapeutic agents to treat diverse kidney diseases. Although TRPC6 has been a major focus for drug discovery, more recent studies suggest that other TRPC family members play a role in the pathogenesis of glomerular disease processes and chronic kidney disease (CKD). This review highlights the data implicating TRPC6 and other TRPC family members in both genetic and non-genetic forms of kidney disease, focusing on TRPC3, TRPC5, and TRPC6 in a cell type (glomerular podocytes) that plays a key role in proteinuric kidney diseases. Full article

(This article belongs to the Special Issue TRPC Channels)

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