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Shmuel Muallem - One of the best experts on this subject based on the ideXlab platform.
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The TRPCs-STIM1-Orai interaction.
Handbook of experimental pharmacology, 2014Co-Authors: Seok Choi, Kyu Pil Lee, Min Seuk Kim, József Maléth, Archana Jha, Malini Ahuja, Shmuel MuallemAbstract:Ca2+ signaling entails receptor-stimulated Ca2+ release from the ER stores that serves as a signal to activate Ca2+ influx channels present at the plasma membrane, the store-operated Ca2+ channels (SOCs). The two known SOCs are the Orai and TRPC channels. The SOC-dependent Ca2+ influx mediates and sustains virtually all Ca2+-dependent regulatory functions. The signal that transmits the Ca2+ content of the ER stores to the plasma membrane is the ER resident, Ca2+-binding protein STIM1. STIM1 is a multidomain protein that clusters and dimerizes in response to Ca2+ store depletion leading to activation of Orai and TRPC channels. Activation of the Orais by STIM1 is obligatory for their function as SOCs, while TRPC channels can function as both STIM1-dependent and STIM1-independent channels. Here we discuss the different mechanisms by which STIM1 activates the Orai and TRPC channels, the emerging specific and non-overlapping physiological functions of Ca2+ influx mediated by the two channel types, and argue that the TRPC channels should be the preferred therapeutic target to control the toxic effect of excess Ca2+ influx.
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The closing and opening of TRPC channels by Homer1 and STIM1.
Acta physiologica (Oxford England), 2011Co-Authors: Joseph P Yuan, Kyu Pil Lee, Jeong Hee Hong, Shmuel MuallemAbstract:Influx of Ca(2+) is a central component of the receptor-evoked Ca(2+) signal. A ubiquitous form of Ca(2+) influx comes from Ca(2+) channels that are activated in response to depletion of the endoplasmic reticulum Ca(2+) stores and are thus named the store-operated Ca(2+) -influx channels (SOCs). One form of SOC is the transient receptor potential canonical (TRPC) channels. A major question in the field of Ca(2+) signalling is the molecular mechanism that regulates the opening and closing of these channels. All TRPC channels have a Homer-binding ligand and two conserved negative charges that interact with two terminal lysines of the stromal interacting molecule 1 (STIM1). The Homer and STIM1 sites are separated by only four amino acid residues. Based on available results, we propose a molecular mechanism by which Homer couples TRPC channels to IP(3) receptors (IP(3) Rs) to keep these channels in the closed state. Dissociation of the TRPCs-Homer-IP(3) Rs complex allows STIM1 access to the TRPC channels negative charges to gate open these channels.
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stim1 dependent and stim1 independent function of transient receptor potential canonical TRPC channels tunes their store operated mode
Journal of Biological Chemistry, 2010Co-Authors: Kyu Pil Lee, Joseph P Yuan, Paul F Worley, Shmuel MuallemAbstract:Ca2+ influx by store-operated Ca2+ channels is a key component of the receptor-evoked Ca2+ signal. In all cells examined, transient receptor potential canonical (TRPC) channels mediate a significant portion of the receptor-stimulated Ca2+ influx. Recent studies have revealed how STIM1 activates TRPC1 in response to store depletion; however, the role of STIM1 in TRPC channel activation by receptor stimulation is not fully understood. Here, we established mutants of TRPC channels that could not be activated by STIM1 but were activated by the “charge-swap” mutant STIM1(K684E,K685E). Significantly, WT but not mutant TRPC channels were inhibited by scavenging STIM1 with Orai1(R91W), indicating the STIM1 dependence and independence of WT and mutant TRPC channels, respectively. Importantly, mutant TRPC channels were robustly activated by receptor stimulation. Moreover, STIM1 and STIM1(K684E,K685E) reciprocally affected receptor-activated WT and mutant TRPC channels. Together, these findings indicate that TRPC channels can function as STIM1-dependent and STIM1-independent channels, which increases the versatility of TRPC channel function and their role in receptor-stimulated Ca2+ influx.
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TRPC channels as stim1 regulated socs
Channels, 2009Co-Authors: Joseph P Yuan, Paul F Worley, Weizhong Zeng, Min Seuk Kim, Dong Min Shin, Guo N Huang, Shmuel MuallemAbstract:Store-operated Ca(2+) channels (SOCs) are Ca(2+) influx channels at the plasma membrane whose opening is determined by the level of Ca(2+) stored in the endoplasmic reticulum lumen. SOCs are activated in response to receptor-mediated or passive depletion of ER Ca(2+) to regulate many Ca(2+)-dependent cellular functions. Early work implicated the TRPC channels as SOCs. More recently, it was found that the Orai channels mediate the CRAC current and that the Ca(2+) binding protein STIM1 functions as the ER Ca(2+) sensor that mediates activation of the SOCs in response to depletion of ER Ca(2+). Key questions are whether both TRPC and Orai channels are opened by STIM1 and the molecular mechanism by which STIM1 opens the SOCs. Ample biochemical and functional evidence indicate interaction of the TRPC channels with STIM1. Furthermore, it was found that STIM1 gates TRPC channels by electrostatic interaction of STIM1(K684,K685) in the polybasic domain of STIM1 with two negative charges (aspartates or glutamates) that are conserved in all TRPC channels. Charge mutants of STIM1(K684,K685) and TRPC1(D639,D640) and TRPC3(D697,D698) were used to develop further direct evidence for the function of TRPC channels as SOCs. The evidence in favor of TRPC channels as SOCs are discussed.
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TRPC channels as STIM1-regulated SOCs.
Channels (Austin Tex.), 2009Co-Authors: Joseph P Yuan, Paul F Worley, Weizhong Zeng, Min Seuk Kim, Dong Min Shin, Guo N Huang, Shmuel MuallemAbstract:Store-operated Ca2+ channels (SOCs) are Ca2+ influx channels at the plasma membrane whose opening is determined by the level of Ca2+ stored in the endoplasmic reticulum lumen. The SOCs are activated in response to receptor-mediated or passive depletion of ER Ca2+ to regulate many Ca2+-dependent cellular functions. Early work implicated the TRPC channels as SOCs. More recently, it was found that the Orai channels mediate the CRAC current and that the Ca2+ binding protein STIM1 functions as the ER Ca2+ sensor that mediates activation of the SOCs in response to depletion of ER Ca2+. Key questions are whether both TRPC channels and the Orais are opened by STIM1 and the molecular mechanism by which STIM1 opens the SOCs. Ample biochemical and functional evidence indicate interaction of the TRPC channels with STIM1. Furthermore, it was found that STIM1 gates TRPC channels by electrostatic interaction of STIM1(K684,K685) in the polybasic domain of STIM1 with two negative charges (aspartates or glutamates) that a...
Joseph P Yuan - One of the best experts on this subject based on the ideXlab platform.
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The closing and opening of TRPC channels by Homer1 and STIM1.
Acta physiologica (Oxford England), 2011Co-Authors: Joseph P Yuan, Kyu Pil Lee, Jeong Hee Hong, Shmuel MuallemAbstract:Influx of Ca(2+) is a central component of the receptor-evoked Ca(2+) signal. A ubiquitous form of Ca(2+) influx comes from Ca(2+) channels that are activated in response to depletion of the endoplasmic reticulum Ca(2+) stores and are thus named the store-operated Ca(2+) -influx channels (SOCs). One form of SOC is the transient receptor potential canonical (TRPC) channels. A major question in the field of Ca(2+) signalling is the molecular mechanism that regulates the opening and closing of these channels. All TRPC channels have a Homer-binding ligand and two conserved negative charges that interact with two terminal lysines of the stromal interacting molecule 1 (STIM1). The Homer and STIM1 sites are separated by only four amino acid residues. Based on available results, we propose a molecular mechanism by which Homer couples TRPC channels to IP(3) receptors (IP(3) Rs) to keep these channels in the closed state. Dissociation of the TRPCs-Homer-IP(3) Rs complex allows STIM1 access to the TRPC channels negative charges to gate open these channels.
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stim1 dependent and stim1 independent function of transient receptor potential canonical TRPC channels tunes their store operated mode
Journal of Biological Chemistry, 2010Co-Authors: Kyu Pil Lee, Joseph P Yuan, Paul F Worley, Shmuel MuallemAbstract:Ca2+ influx by store-operated Ca2+ channels is a key component of the receptor-evoked Ca2+ signal. In all cells examined, transient receptor potential canonical (TRPC) channels mediate a significant portion of the receptor-stimulated Ca2+ influx. Recent studies have revealed how STIM1 activates TRPC1 in response to store depletion; however, the role of STIM1 in TRPC channel activation by receptor stimulation is not fully understood. Here, we established mutants of TRPC channels that could not be activated by STIM1 but were activated by the “charge-swap” mutant STIM1(K684E,K685E). Significantly, WT but not mutant TRPC channels were inhibited by scavenging STIM1 with Orai1(R91W), indicating the STIM1 dependence and independence of WT and mutant TRPC channels, respectively. Importantly, mutant TRPC channels were robustly activated by receptor stimulation. Moreover, STIM1 and STIM1(K684E,K685E) reciprocally affected receptor-activated WT and mutant TRPC channels. Together, these findings indicate that TRPC channels can function as STIM1-dependent and STIM1-independent channels, which increases the versatility of TRPC channel function and their role in receptor-stimulated Ca2+ influx.
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TRPC channels as stim1 regulated socs
Channels, 2009Co-Authors: Joseph P Yuan, Paul F Worley, Weizhong Zeng, Min Seuk Kim, Dong Min Shin, Guo N Huang, Shmuel MuallemAbstract:Store-operated Ca(2+) channels (SOCs) are Ca(2+) influx channels at the plasma membrane whose opening is determined by the level of Ca(2+) stored in the endoplasmic reticulum lumen. SOCs are activated in response to receptor-mediated or passive depletion of ER Ca(2+) to regulate many Ca(2+)-dependent cellular functions. Early work implicated the TRPC channels as SOCs. More recently, it was found that the Orai channels mediate the CRAC current and that the Ca(2+) binding protein STIM1 functions as the ER Ca(2+) sensor that mediates activation of the SOCs in response to depletion of ER Ca(2+). Key questions are whether both TRPC and Orai channels are opened by STIM1 and the molecular mechanism by which STIM1 opens the SOCs. Ample biochemical and functional evidence indicate interaction of the TRPC channels with STIM1. Furthermore, it was found that STIM1 gates TRPC channels by electrostatic interaction of STIM1(K684,K685) in the polybasic domain of STIM1 with two negative charges (aspartates or glutamates) that are conserved in all TRPC channels. Charge mutants of STIM1(K684,K685) and TRPC1(D639,D640) and TRPC3(D697,D698) were used to develop further direct evidence for the function of TRPC channels as SOCs. The evidence in favor of TRPC channels as SOCs are discussed.
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TRPC channels as STIM1-regulated SOCs.
Channels (Austin Tex.), 2009Co-Authors: Joseph P Yuan, Paul F Worley, Weizhong Zeng, Min Seuk Kim, Dong Min Shin, Guo N Huang, Shmuel MuallemAbstract:Store-operated Ca2+ channels (SOCs) are Ca2+ influx channels at the plasma membrane whose opening is determined by the level of Ca2+ stored in the endoplasmic reticulum lumen. The SOCs are activated in response to receptor-mediated or passive depletion of ER Ca2+ to regulate many Ca2+-dependent cellular functions. Early work implicated the TRPC channels as SOCs. More recently, it was found that the Orai channels mediate the CRAC current and that the Ca2+ binding protein STIM1 functions as the ER Ca2+ sensor that mediates activation of the SOCs in response to depletion of ER Ca2+. Key questions are whether both TRPC channels and the Orais are opened by STIM1 and the molecular mechanism by which STIM1 opens the SOCs. Ample biochemical and functional evidence indicate interaction of the TRPC channels with STIM1. Furthermore, it was found that STIM1 gates TRPC channels by electrostatic interaction of STIM1(K684,K685) in the polybasic domain of STIM1 with two negative charges (aspartates or glutamates) that a...
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TRPC channels as STIM1-regulated store-operated channels.
Cell calcium, 2007Co-Authors: Paul F Worley, Joseph P Yuan, Weizhong Zeng, Guo N Huang, Joo Young Kim, Min Goo Lee, Shmuel MuallemAbstract:Receptor-activated Ca(2+) influx is mediated largely by store-operated channels (SOCs). TRPC channels mediate a significant portion of the receptor-activated Ca(2+) influx. However, whether any of the TRPC channels function as a SOC remains controversial. Our understanding of the regulation of TRPC channels and their function as SOCs is being reshaped with the discovery of the role of STIM1 in the regulation of Ca(2+) influx channels. The findings that STIM1 is an ER resident Ca(2+) binding protein that regulates SOCs allow an expanded and molecular definition of SOCs. SOCs can be considered as channels that are regulated by STIM1 and require the clustering of STIM1 in response to depletion of the ER Ca(2+) stores and its translocation towards the plasma membrane. TRPC1 and other TRPC channels fulfill these criteria. STIM1 binds to TRPC1, TRPC2, TRPC4 and TRPC5 but not to TRPC3, TRPC6 and TRPC7, and STIM1 regulates TRPC1 channel activity. Structure-function analysis reveals that the C-terminus of STIM1 contains the binding and gating function of STIM1. The ERM domain of STIM1 binds to TRPC channels and a lysine-rich region participates in the gating of SOCs and TRPC1. Knock-down of STIM1 by siRNA and prevention of its translocation to the plasma membrane inhibit the activity of native SOCs and TRPC1. These findings support the conclusion that TRPC1 is a SOC. Similar studies with other TRPC channels demonstrate their regulation by STIM1 and indicate that all TRPC channels, except TRPC7, function as SOCs.
Mohamed Trebak - One of the best experts on this subject based on the ideXlab platform.
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TRPC channels in smooth muscle cells.
Frontiers in bioscience (Landmark edition), 2010Co-Authors: José C. González-cobos, Mohamed TrebakAbstract:Transient receptor potential canonical (TRPC) proteins constitute a family of seven (TRPC1-7) nonselective cation channels within the wider TRP superfamily. TRPC1, TRPC3, TRPC4, TRPC5 and TRPC6 channels are expressed in vascular smooth muscle cells from human vessels of all calibers and in smooth muscle from organs such as the uterus and the gastrointestinal tract. TRPC channels have recently emerged as important players in the control of smooth muscle function. This review will focus on the retrospective analysis of studies proposing contributions of TRPC channels to native calcium entry pathways in smooth muscle and to physiological and pathophysiological responses with emphasis on the vascular system.
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Phospholipase C-coupled receptors and activation of TRPC channels.
Handbook of experimental pharmacology, 2007Co-Authors: Mohamed Trebak, Loic Lemonnier, Jeremy T. Smyth, Guillermo Vazquez, James W. PutneyAbstract:The canonical transient receptor potential (TRPC) cation channels are mammalian homologs of the photoreceptor channel TRP in Drosophila melanogaster. All seven TRPCs (TRPC1 through TRPC7) can be activated through Gq/11 receptors or receptor tyrosine kinase (RTK) by mechanisms downstream of phospholipase C. The last decade saw a rapidly growing interest in understanding the role of TRPC channels in calcium entry pathways as well as in understanding the signal(s) responsible for TRPC activation. TRPC channels have been proposed to be activated by a variety of signals including store depletion, membrane lipids, and vesicular insertion into the plasma membrane. Here we discuss recent developments in the mode of activation as well as the pharmacological and electrophysiological properties of this important and ubiquitous family of cation channels.
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The mammalian TRPC cation channels.
Biochimica et Biophysica Acta, 2004Co-Authors: Guillermo Vazquez, Mohamed Trebak, Barbara J. Wedel, Omar Aziz, James W. PutneyAbstract:Transient Receptor Potential-Canonical (TRPC) channels are mammalian homologs of Transient Receptor Potential (TRP), a Ca 2+ permeable channel involved in the phospholipase C-regulated photoreceptor activation mechanism in Drosophila. The seven mammalian TRPCs constitute a family of channels which have been proposed to function as store-operated as well as second messenger-operated channels in a variety of cell types. TRPC channels, together with other more distantly related channel families, make up the larger TRP channel superfamily. This review summarizes recent findings on the structure, regulation and function of the apparently ubiquitous TRPC cation channels. Published by Elsevier B.V.
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The mammalian TRPC cation channels
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2004Co-Authors: Guillermo Vazquez, Mohamed Trebak, Barbara J. Wedel, Omar Aziz, James W. PutneyAbstract:AbstractTransient Receptor Potential-Canonical (TRPC) channels are mammalian homologs of Transient Receptor Potential (TRP), a Ca2+-permeable channel involved in the phospholipase C-regulated photoreceptor activation mechanism in Drosophila. The seven mammalian TRPCs constitute a family of channels which have been proposed to function as store-operated as well as second messenger-operated channels in a variety of cell types. TRPC channels, together with other more distantly related channel families, make up the larger TRP channel superfamily. This review summarizes recent findings on the structure, regulation and function of the apparently ubiquitous TRPC cation channels
James W. Putney - One of the best experts on this subject based on the ideXlab platform.
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Phospholipase C-coupled receptors and activation of TRPC channels.
Handbook of experimental pharmacology, 2007Co-Authors: Mohamed Trebak, Loic Lemonnier, Jeremy T. Smyth, Guillermo Vazquez, James W. PutneyAbstract:The canonical transient receptor potential (TRPC) cation channels are mammalian homologs of the photoreceptor channel TRP in Drosophila melanogaster. All seven TRPCs (TRPC1 through TRPC7) can be activated through Gq/11 receptors or receptor tyrosine kinase (RTK) by mechanisms downstream of phospholipase C. The last decade saw a rapidly growing interest in understanding the role of TRPC channels in calcium entry pathways as well as in understanding the signal(s) responsible for TRPC activation. TRPC channels have been proposed to be activated by a variety of signals including store depletion, membrane lipids, and vesicular insertion into the plasma membrane. Here we discuss recent developments in the mode of activation as well as the pharmacological and electrophysiological properties of this important and ubiquitous family of cation channels.
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The mammalian TRPC cation channels.
Biochimica et Biophysica Acta, 2004Co-Authors: Guillermo Vazquez, Mohamed Trebak, Barbara J. Wedel, Omar Aziz, James W. PutneyAbstract:Transient Receptor Potential-Canonical (TRPC) channels are mammalian homologs of Transient Receptor Potential (TRP), a Ca 2+ permeable channel involved in the phospholipase C-regulated photoreceptor activation mechanism in Drosophila. The seven mammalian TRPCs constitute a family of channels which have been proposed to function as store-operated as well as second messenger-operated channels in a variety of cell types. TRPC channels, together with other more distantly related channel families, make up the larger TRP channel superfamily. This review summarizes recent findings on the structure, regulation and function of the apparently ubiquitous TRPC cation channels. Published by Elsevier B.V.
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The mammalian TRPC cation channels
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2004Co-Authors: Guillermo Vazquez, Mohamed Trebak, Barbara J. Wedel, Omar Aziz, James W. PutneyAbstract:AbstractTransient Receptor Potential-Canonical (TRPC) channels are mammalian homologs of Transient Receptor Potential (TRP), a Ca2+-permeable channel involved in the phospholipase C-regulated photoreceptor activation mechanism in Drosophila. The seven mammalian TRPCs constitute a family of channels which have been proposed to function as store-operated as well as second messenger-operated channels in a variety of cell types. TRPC channels, together with other more distantly related channel families, make up the larger TRP channel superfamily. This review summarizes recent findings on the structure, regulation and function of the apparently ubiquitous TRPC cation channels
Indu S. Ambudkar - One of the best experts on this subject based on the ideXlab platform.
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Role of TRPC Channels in Store-Operated Calcium Entry.
Advances in experimental medicine and biology, 2016Co-Authors: Hwei Ling Ong, Lorena Brito De Souza, Indu S. AmbudkarAbstract:Store-operated calcium entry (SOCE) is a ubiquitous Ca2+ entry pathway that is activated in response to depletion of Ca2+ stores within the endoplasmic reticulum (ER) and contributes to the control of various physiological functions in a wide variety of cell types. The transient receptor potential canonical (TRPC) channels (TRPCs 1–7), that are activated by stimuli leading to PIP2 hydrolysis, were first identified as molecular components of SOCE channels. TRPC channels show a miscellany of tissue expression, physiological functions and channel properties. However, none of the TRPC members display currents that resemble ICRAC. Intensive search for the CRAC channel component led to identification of Orai1 and STIM1, now established as being the primary constituents of the CRAC channel. There is now considerable evidence that STIM1 activates both Orai1 and TRPC1 via distinct domains in its C-terminus. Intriguingly, TRPC1 function is not only dependent on STIM1 but also requires Orai1. The critical functional interaction between TRPC1 and Orai1, which determines the activation of TRPC1, has also been identified. In this review, we will discuss current concepts regarding the role of TRPC channels in SOCE, the physiological functions regulated by TRPC-mediated SOCE, and the complex mechanisms underlying the regulation of TRPCs, including the functional interactions with Orai1 and STIM1.
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Trafficking mechanisms and regulation of TRPC channels.
Cell calcium, 2014Co-Authors: Lorena Brito De Souza, Indu S. AmbudkarAbstract:TRPC channels are Ca2+-permeable cation channels which are regulated downstream from receptor-coupled PIP2 hydrolysis. These channels contribute to a wide variety of cellular functions. Loss or gain of channel function has been associated with dysfunction and aberrant physiology. TRPC channel functions are influenced by their physical and functional interactions with numerous proteins that determine their regulation, scaffolding, trafficking, as well as their effects on the downstream cellular processes. Such interactions also compartmentalize the Ca2+ signals arising from TRPC channels. A large number of studies demonstrate that trafficking is a critical mode by which plasma membrane localization and surface expression of TRPC channels are regulated. This review will provide an overview of intracellular trafficking pathways as well as discuss the current state of knowledge regarding the mechanisms and components involved in trafficking of the seven members of the TRPC family (TRPC1–TRPC7).
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Physiological functions and regulation of TRPC channels.
Handbook of experimental pharmacology, 2014Co-Authors: Hwei Ling Ong, Lorena Brito De Souza, Kwong Tai Cheng, Indu S. AmbudkarAbstract:The TRP-canonical (TRPC) subfamily, which consists of seven members (TRPC1–TRPC7), are Ca2+-permeable cation channels that are activated in response to receptor-mediated PIP2 hydrolysis via store-dependent and store-independent mechanisms. These channels are involved in a variety of physiological functions in different cell types and tissues. Of these, TRPC6 has been linked to a channelopathy resulting in human disease. Two key players of the store-dependent regulatory pathway, STIM1 and Orai1, interact with some TRPC channels to gate and regulate channel activity. The Ca2+ influx mediated by TRPC channels generates distinct intracellular Ca2+ signals that regulate downstream signaling events and consequent cell functions. This requires localization of TRPC channels in specific plasma membrane microdomains and precise regulation of channel function which is coordinated by various scaffolding, trafficking, and regulatory proteins.
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Organization and function of TRPC channelosomes
Pflügers Archiv - European Journal of Physiology, 2007Co-Authors: Indu S. AmbudkarAbstract:TRPC proteins constitute a family of conserved Ca^2+-permeable cation channels which are activated in response to agonist-stimulated PIP_2 hydrolysis. These channels were initially proposed to be components of the store-operated calcium entry channel (SOC). Subsequent studies have provided substantial evidence that some TRPCs contribute to SOC activity. TRPC proteins have also been shown to form agonist-stimulated calcium entry channels that are not store-operated but are likely regulated by PIP_2 or diacylglycerol. Further, and consistent with the presently available data, selective homomeric or heteromeric interactions between TRPC monomers generate distinct agonist-stimulated cation permeable channels. We suggest that interaction between TRPC monomers, as well as the association of these channels with accessory proteins, determines their mode of regulation as well as their cellular localization and function. Currently identified accessory proteins include key Ca^2+ signaling proteins as well as proteins involved in vesicle trafficking, cytoskeletal interactions, and scaffolding. Studies reported until now demonstrate that TRPC proteins are segregated into specific Ca^2+ signaling complexes which can generate spatially and temporally controlled [Ca^2+]_i signals. Thus, the functional organization of TRPC channelosomes dictates not only their regulation by extracellular stimuli but also serves as a platform to coordinate specific downstream cellular functions that are regulated as a consequence of Ca^2+ entry. This review will focus on the accessory proteins of TRPC channels and discuss the functional implications of TRPC channelosomes and their assembly in microdomains.
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Ca2+ signaling microdomains:platforms for the assembly andregulation of TRPC channels
Trends in pharmacological sciences, 2005Co-Authors: Indu S. AmbudkarAbstract:The transient receptor potential canonical family (TRPC1–TRPC7) of ion channel proteins, which are activated in response to agonist-stimulated phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5) P 2 ] hydrolysis, are proposed components of the elusive store-operated Ca 2+ (SOC) channel. TRPC channels display distinct properties and interact to form homomeric or heteromeric channels that differ in their function and regulation. Although the exact function of TRPC channels and how they are regulated has not been established, increasing data suggest that they are localized and regulated within Ca 2+ signaling microdomains. TRPC channels contribute to store-operated and store-independent Ca 2+ entry mechanisms, both of which are activated by agonist-stimulated PtdIns(4,5) P 2 hydrolysis. Elucidation of how cells achieve specificity and precise temporal and spatial coordination of channel activation is crucial for understanding the molecular basis of agonist-mediated stimulation of Ca 2+ entry and identifying downstream physiological functions. This review will address the assembly and localization of TRPC channels and how these processes impact their function.
