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The TRPC3/6/7 subfamily of cation channels.

The mammalian transient receptor potential (TRP) proteins consist of a superfamily of Ca2+-permeant non-selective cation channels with structural similarities to Drosophila TRP. The TRP superfamily can be divided into three major families, among them the "canonical TRP" family (TRPC). The seven protein products of the mammalian TRPC family of genes (designated TRPC1-7) share in common the activation through PLC-coupled receptors and have been proposed to encode components of native store-operated channels in different cell types. In addition, the three members of the TRPC3/6/7 subfamily of TRPC channels can be activated by diacylglycerol analogs, providing a possible mechanism of activation of these channels by PLC-coupled receptors. This review summarizes the current knowledge about the mechanism of activation of the TRPC3/6/7 subfamily, as well as the potential role of these proteins as components of native Ca2+-permeant channels.

Animals↗
PubMed2007

Ionic channels formed by TRPC4.

TRPC4 (transient receptor potential canonical 4) is a member of the TRPC sub-family and, within this sub-family, TRPC4 is most closely related to TRPC5. A number of splice variants of TRPC4 have been identified, whereby TRPC4alpha and TRPC4beta appear to be the most abundant isoforms in various species. TRPC4alpha comprises six transmembrane segments and the N- and C-termini are located intracellularly. Additionally, TRPC4alpha shares other structural features with members of the TRPC sub-group, including ankyrin-like repeats, coiled-coil regions and binding sites for calmodulin and IP3 receptors. Three calmodulin-binding domains have been identified in the C-terminus of TRPC4alpha. TRPC4beta lack 84 amino acids in the C-terminus, which correspond to the last two calmodulin-binding sites of TRPCalpha. The first and last calmodulin-binding domains of TRPC4alpha overlap with binding sites for the N- and C-termini of IP3 receptors. The ionic channels formed by TRPC4 appear to be Ca(2+)-permeable, although there is a considerably discrepancy in the degree of Ca2+ selectivity. Studies with mice lacking TRPC4 (TRPC4(-/-)) suggest an important role for TRPC4 in supporting Ca2+ entry. The defect in Ca2+ entry in TRPC4(-/-) mice appears to be associated with a reduction of the vasorelaxation of arteries, vascular permeability in the lung and neurotransmitter release from thalamic dendrites.

Amino Acids↗
PubMed1996

Calcium signalling: setting store by calcium channels.

Recent work, stemming from genetic studies of phototransduction in Drosophila, has identified a set of homologous channel proteins that appear to mediate capacitative Ca2+ entry in species from worms and files to humans.

Animals↗
PubMed2006

Functional coupling between TRPC3 and RyR1 regulates the expressions of key triadic proteins.

We have shown that TRPC3 (transient receptor potential channel canonical type 3) is sharply up-regulated during the early part of myotube differentiation and remains elevated in mature myotubes compared with myoblasts. To examine its functional roles in muscle, TRPC3 was "knocked down" in mouse primary skeletal myoblasts using retroviral-delivered small interference RNAs and single cell cloning. TRPC3 knockdown myoblasts (97.6 +/- 1.9% reduction in mRNA) were differentiated into myotubes (TRPC3 KD) and subjected to functional and biochemical assays. By measuring rates of Mn(2+) influx with Fura-2 and Ca(2+) transients with Fluo-4, we found that neither excitation-coupled Ca(2+) entry nor thapsigargin-induced store-operated Ca(2+) entry was significantly altered in TRPC3 KD, indicating that expression of TRPC3 is not required for engaging either Ca(2+) entry mechanism. In Ca(2+) imaging experiments, the gain of excitation-contraction coupling and the amplitude of the Ca(2+) release seen after direct RyR1 activation with caffeine was significantly reduced in TRPC3 KD. The decreased gain appears to be due to a decrease in RyR1 Ca(2+) release channel activity, because sarcoplasmic reticulum (SR) Ca(2+) content was not different between TRPC3 KD and wild-type myotubes. Immunoblot analysis demonstrated that TRPC1, calsequestrin, triadin, and junctophilin 1 were up-regulated (1.46 +/- 1.91-, 1.42 +/- 0.08-, 2.99 +/- 0.32-, and 1.91 +/- 0.26-fold, respectively) in TRPC3 KD. Based on these data, we conclude that expression of TRPC3 is tightly regulated during muscle cell differentiation and propose that functional interaction between TRPC3 and RyR1 may regulate the gain of SR Ca(2+) release independent of SR Ca(2+) load.

Acetylcysteine↗
PubMed2005

TRPC1 functions as a store-operated Ca2+ channel in intestinal epithelial cells and regulates early mucosal restitution after wounding.

An increase in cytosolic free Ca(2+) concentration ([Ca(2+)](cyt)) results from Ca(2+) release from intracellular stores and extracellular Ca(2+) influx through Ca(2+)-permeable ion channels and is crucial for initiating intestinal epithelial restitution to reseal superficial wounds after mucosal injury. Capacitative Ca(2+) entry (CCE) induced by Ca(2+) store depletion represents a major Ca(2+) influx mechanism, but the exact molecular components constituting this process remain elusive. This study determined whether canonical transient receptor potential (TRPC)1 served as a candidate protein for Ca(2+)-permeable channels mediating CCE in intestinal epithelial cells and played an important role in early epithelial restitution. Normal intestinal epithelial cells (the IEC-6 cell line) expressed TRPC1 and TPRC5 and displayed typical records of whole cell store-operated Ca(2+) currents and CCE generated by Ca(2+) influx after depletion of intracellular stores. Induced TRPC1 expression by stable transfection with the TRPC1 gene increased CCE and enhanced cell migration during restitution. Differentiated IEC-Cdx2L1 cells induced by forced expression of the Cdx2 gene highly expressed endogenous TRPC1 and TRPC5 and exhibited increased CCE and cell migration. Inhibition of TRPC1 expression by small interfering RNA specially targeting TRPC1 not only reduced CCE but also inhibited cell migration after wounding. These findings strongly suggest that TRPC1 functions as store-operated Ca(2+) channels and plays a critical role in intestinal epithelial restitution by regulating CCE and intracellular [Ca(2+)](cyt).

Animals↗
PubMed2006

TRP channels, CCE, and the pulmonary vascular smooth muscle.

Transient receptor potential (TRP) genes represent a novel class of genes that are generally believed to encode for nonselective cation channels. A subfamily of TRP channels, canonical TRP (TRPC), which are highly permeable to Ca2+ (and Na+), co-assembles with each other to form functional store- and receptor-operated Ca2+ channels. TRPC mRNA and protein have been identified in pulmonary arterial smooth muscle and endothelial cells. The currents generated by Ca2+ influx through store- and receptor-operated Ca2+ channels have also been extensively characterized in these cells. More recently, the attention has shifted to identify the TRP subunits that underlie the function of native channels in the pulmonary vasculature, with the understanding that TRP channels assemble as either homo-or heterotetramers in vivo. This work in progress has yielded exciting information regarding the involvement of TRP channels in the control of smooth muscle contraction, and cell proliferation and migration. In this review, the authors focus on describing the function and transcriptional regulation of TRP proteins, and the store- and receptor-operated Ca2+ channels for which they are responsible, in pulmonary artery smooth muscle cells (PASMC). They also identify some key TRP proteins whose role in the pulmonary vasculature has been established, as well as some more novel subunits whose role, although intriguing, can only be inferred from other vascular studies. Finally, they describe the involvement of TRP channels in regulating pulmonary vasoconstriction, PASMC proliferation, and pulmonary endothelial barrier function.

Animals↗
PubMed2006

Functional organization of TRPC-Ca2+ channels and regulation of calcium microdomains.

TRP family of proteins are components of unique cation channels that are activated in response to diverse stimuli ranging from growth factor and neurotransmitter stimulation of plasma membrane receptors to a variety of chemical and sensory signals. This review will focus on members of the TRPC sub-family (TRPC1-TRPC7) which currently appear to be the strongest candidates for the enigmatic Ca(2+) influx channels that are activated in response to stimulation of plasma membrane receptors which result in phosphatidyl inositol-(4,5)-bisphosphate (PIP(2)) hydrolysis, generation of IP(3) and DAG, and IP(3)-induced Ca(2+) release from the intracellular Ca(2+) store via inositol trisphosphate receptor (IP(3)R). Homomeric or selective heteromeric interactions between TRPC monomers generate distinct channels that contribute to store-operated as well as store-independent Ca(2+) entry mechanisms. The former is regulated by the emptying/refilling of internal Ca(2+) store(s) while the latter depends on PIP(2) hydrolysis (due to changes in PIP(2) per se or an increase in diacylglycerol, DAG). Although the exact physiological function of TRPC channels and how they are regulated has not yet been conclusively established, it is clear that a variety of cellular functions are controlled by Ca(2+) entry via these channels. Thus, it is critical to understand how cells coordinate the regulation of diverse TRPC channels to elicit specific physiological functions. It is now well established that segregation of TRPC channels mediated by interactions with signaling and scaffolding proteins, determines their localization and regulation in functionally distinct cellular domains. Furthermore, both protein and lipid components of intracellular and plasma membranes contribute to the organization of these microdomains. Such organization serves as a platform for the generation of spatially and temporally dictated [Ca(2+)](i) signals which are critical for precise control of downstream cellular functions.

Animals↗
PubMed2005

The diacylgylcerol-sensitive TRPC3/6/7 subfamily of cation channels: functional characterization and physiological relevance.

Among the "classical" or "canonical" transient receptor potential (TRPC) family, the TRPC3, -6, and -7 channels share 75% amino acid identity and are gated by exposure to diacylglycerol. TRPC3, TRPC6, and TRPC7 interact physically and coassemble to form functional tetrameric channels. This review focuses on the TRPC3/6/7 subfamily and describes their functional properties and regulation as homomers obtained from overexpression studies in cell lines. It also summarizes their heteromultimerization potential in vitro and in vivo and presents initial data concerning their physiological functions analyzed in isolated tissues with downregulated channel activity and gene-deficient mouse models.

Animals↗
PubMed1999

Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol.

Eukaryotic cells respond to many hormones and neurotransmitters with increased activity of the enzyme phospholipase C and a subsequent rise in the concentration of intracellular free calcium ([Ca2+]i). The increase in [Ca2+]i occurs as a result of the release of Ca2+ from intracellular stores and an influx of Ca2+ through the plasma membrane; this influx of Ca2+ may or may not be store-dependent. Drosophila transient receptor potential (TRP) proteins and some mammalian homologues (TRPC proteins) are thought to mediate capacitative Ca2+ entry. Here we describe the molecular mechanism of store-depletion-independent activation of a subfamily of mammalian TRPC channels. We find that hTRPC6 is a non-selective cation channel that is activated by diacylglycerol in a membrane-delimited fashion, independently of protein kinases C activated by diacylglycerol. Although hTRPC3, the closest structural relative of hTRPC6, is activated in the same way, TRPCs 1, 4 and 5 and the vanilloid receptor subtype 1 are unresponsive to the lipid mediator. Thus, hTRPC3 and hTRPC6 represent the first members of a new functional family of second-messenger-operated cation channels, which are activated by diacylglycerol.

Animals↗
PubMed2007

TRPC1 Ca(2+)-permeable channels in animal cells.

The full-length transient receptor (TRPC)1 polypeptide is composed of about 790 amino acids, and several splice variants are known. The predicted structure and topology is of an integral membrane protein composed of six transmembrane domains, and a cytoplasmic C- and N-terminal domain. The N-terminal domain includes three ankyrin repeat motifs. Antibodies which recognise TRPC1 have been developed, but it has been difficult to obtain antibodies which have high affinity and specificity for TRPC1. This has made studies of the cellular functions of TRPC1 somewhat difficult. The TRPC1 protein is widely expressed in different types of animal cells, and within a given cell is found at the plasma membrane and at intracellular sites. TRPC1 interacts with calmodulin, caveolin-1, the InsP3 receptor, Homer, phospholipase C and several other proteins. Investigations of the biological roles and mechanisms of action of TRPC1 have employed ectopic (over-expression or heterologous expression) of the polypeptide in addition to studies of endogenous TRPC1. Both approaches have encountered difficulties. TRPC1 forms heterotetramers with other TRPC polypeptides resulting in cation channels which are non-selective. TRPC1 may be: a component of the pore of store-operated Ca2+ channels (SOCs); a subsidiary protein in the pathway of activation of SOCs; activated by interaction with InsP3R; and/or activated by stretch. Further experiments are required to resolve the exact roles and mechanisms of activation of TRPC1. Cation entry through the TRPC1 channel is feed-back inhibited by Ca2+ through interaction with calmodulin, and is inhibited by Gd3+, La3+, SKF96365 and 2-APB, and by antibodies targeted to the external mouth of the TRPC1 pore. Activation of TRPC1 leads to the entry to the cytoplasmic space of substantial amounts of Na+ as well as Ca2+. A requirement for TRPC1 is implicated in numerous downstream cellular pathways. The most clearly described roles are in the regulation of growth cone turning in neurons. It is concluded that TRPC1 is a most interesting protein because of the apparent wide variety of its roles and functions and the challenges posed to those attempting to elucidate its primary intracellular functions and mechanisms of action.

Animals↗
PubMed2005

Induction of intracellular calcium elevation by Delta9-tetrahydrocannabinol in T cells involves TRPC1 channels.

We have reported previously that Delta9-tetrahydrocannabinol (Delta9-THC) treatment of resting human and murine splenic T cells robustly elevated intracellular calcium ([Ca2+]i). The objective of the present investigation was to examine the putative role of [Ca2+]i store depletion and store-operated calcium (SOC) and receptor-operated cation (ROC) channels in the mechanism by which Delta9-THC increases [Ca2+]i in the cannabinoid-2 receptor-expressing human peripheral blood-acute lymphoid leukemia (HPB-ALL) human T cell line. By using the smooth endoplasmic reticulum Ca2+-ATPase pump inhibitor, thapsigargin, and the ryanodine receptor antagonist, 8-bromo-cyclic adenosine diphosphate ribose, we demonstrate that the Delta9-THC-mediated elevation in [Ca2+]i occurs independently of [Ca2+]i store depletion. Furthermore, the ROC channel inhibitor, SK&F 96365 was more efficacious at attenuating the Delta9-THC-mediated elevation in [Ca2+]i than SOC channel inhibitors, 2-aminoethoxydiphenyl borate and La3+. Recently, several members of the transient receptor potential canonical (TRPC) channel subfamily have been suggested to operate as SOC or ROC channels. In the present studies, treatment of HPB-ALL cells with 1-oleoyl-2-acetyl-sn-glycerol (OAG), a cell-permeant analog of diacylglycerol (DAG), which gates several members of the TRPC channel subfamily, rapidly elevated [Ca2+]i, as well as prevented a subsequent, additive elevation in [Ca2+]i by Delta9-THC, independent of protein kinase C. Reverse transcriptase-polymerase chain reaction analysis for TRPC1-7 showed that HPB-ALL cells express detectable mRNA levels of only TRPC1. Finally, small interference RNA knockdown of TRPC1 attenuated the Delta9-THC-mediated elevation of [Ca2+]i. Collectively, these results suggest that Delta9-THC-induced elevation in [Ca2+]i is attributable entirely to extracellular calcium influx, which is independent of [Ca2+]i store depletion, and is mediated, at least partially, through the DAG-sensitive TRPC1 channels.

Analgesics, Non-Narcotic↗
PubMed2001

Dissecting receptor-mediated Ca2+ influx pathways: TRP channels and their native counterparts.

Cellular stimulation from the surrounding extracellular environment via receptors and other pathways evoke activation of Ca2+-permeable cation channels that form essential signaling pathways in controlling biological responses. An important clue to understand the molecular mechanisms underlying these cation channels (tentatively termed as receptor-mediated cation channels (RMCC)) was first provided through molecular studies of the transient receptor potential (trp) protein (TRP), which controls light-induced depolarization in Drosophila photoreceptor cells. Use of the genetic information and recombinant expression technique lead to the discovery of numerous mammalian TRP homologues revealing novel RMCCs. In this review, we focus on the dramatic progress in the molecular investigation of RMCC in mammalian systems. The recent findings should provide powerful tools for the development of novel pharmaceutical targets.

Animals↗
PubMed2003

International Union of Pharmacology. XLIII. Compendium of voltage-gated ion channels: transient receptor potential channels.

The transient receptor potential (TRP) proteins are six transmembrane-containing subunits that combine to form cation-selective ion channels. TRP channels are present in yeast, Drosophila, Caenorhabditis elegans, and mammals. They are widely distributed and sense local changes in stimuli ranging from light to temperature and osmolarity. Mammals contain at least 22 distinct genes encoding these ion channels. This summary article presents an overview of the molecular relationships among the TRP channels and a standard nomenclature for them, which is derived from the IUPHAR Compendium of Voltage-Gated Ion Channels. The complete Compendium, including data tables for each member of the TRP channel family, can be found at http://www.iuphar-db.org/iuphar-ic/.

Animals↗
PubMed2002

The TRP family of cation channels: probing and advancing the concepts on receptor-activated calcium entry.

Stimulation of membrane receptors linked to a phospholipase C and the subsequent production of the second messengers diacylglycerol and inositol-1,4,5-trisphosphate (InsP(3)) is a signaling pathway of fundamental importance in eukaryotic cells. Signaling downstream of these initial steps involves mobilization of Ca(2+) from intracellular stores and Ca(2+) influx through the plasma membrane. For this influx, several contrasting mechanisms may be responsible but particular relevance is attributed to the induction of Ca(2+) influx as consequence of depletion of intracellular calcium stores. This phenomenon (frequently named store-operated calcium entry, SOCE), in turn, may be brought about by various signals, including soluble cytosolic factors, interaction of proteins of the endoplasmic reticulum with ion channels in the plasma membrane, and a secretion-like coupling involving translocation of channels to the plasma membrane. Experimental approaches to analyze these mechanisms have been considerably advanced by the discovery of mammalian homologs of the Drosophila cation channel transient receptor potential (TRP). Some members of the TRP family can be expressed to Ca(2+)-permeable channels that enable SOCE; other members form channels activated independently of stores. TRP proteins may be an essential part of endogenous Ca(2+) entry channels but so far expression of most TRP cDNAs has not resulted in restitution of channels found in any mammalian cells, suggesting the requirement for further unknown subunits. A major exception is CaT1, a TRP channel demonstrated to provide Ca(2+)-selective, store-operated currents identical to those characterized in several cell types. Ongoing and future research on TRP channels will be crucial to understand the molecular basis of receptor-mediated Ca(2+) entry, with respect to the structure of the entry channels as well as to the mechanisms of its activation and regulation.

Animals↗
PubMed2005

Canonical transient receptor potential channel 4 (TRPC4) co-localizes with the scaffolding protein ZO-1 in human fetal astrocytes in culture.

Members of the mammalian transient receptor potential (TRP) family form cation-permeable channels at the plasma membrane implicated in capacitative calcium influx after activation by either second-messenger-mediated pathways or store depletion, or both. This study shows that with the use of RT-PCR, Western blotting, and immunohistochemistry, resting astrocytes express TRPC4 at the cell membrane, particularly at sites of cell-to-cell contact. By confocal imaging and immunoelectron microscopy, we detected co-localization of TRPC4 with the scaffolding protein zonula occludens 1 (ZO-1), and demonstrated that immunoprecipitation with antibodies to ZO-1 brought down TRPC4, and vice-versa. It has been proposed that the targeting of TRPC4 to the cell membrane is dependent on the interaction of the C-terminal TRL motif with PDZ domains. Using transfection of astrocytes with myc-tagged TRPC4 or TRL-motif truncated TRPC4 (deltaTRL), we found that deltaTRL localized predominantly to a juxtanuclear compartment, whereas the wild-type protein showed cell surface distribution. Deletion of the TRL motif also reduced plasma membrane expression as assessed by cell surface biotinylation experiments. Using GST fusion proteins, we found that TRPC4 interacted with the PDZ1 domain of ZO-1 and that this was also dependent on the TRL motif. Thus, our data demonstrate that the PDZ-interacting domain of TRPC4 controls its cell surface localization. These data implicate TRPC4 in the regulation of calcium homeostasis in astrocytes, particularly as part of a signaling complex that forms at junctional sites between astrocytes.

Astrocytes↗