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

Dietrich, Alexander; Kalwa, Hermann; Rost, Benjamin R.; Gudermann, Thomas

doi:10.1007/s00424-005-1460-0

Cited by 132 publications

(104 citation statements)

References 86 publications

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“…Deletion of TRPC6 in mice resulted in the up-regulation of TRPC3 expression in vascular smooth muscle cells (44), which could interfere with the interpretation of our data. Human endothelial cells were shown to abundantly express TRPC6 mRNA and TRPC3 to a lesser extent (18).…”

Section: Discussionmentioning

confidence: 92%

Gαq-TRPC6-mediated Ca2+ Entry Induces RhoA Activation and Resultant Endothelial Cell Shape Change in Response to Thrombin

Singh

Knezevic

Ahmmed

et al. 2007

Journal of Biological Chemistry

202

215

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Section: Discussionmentioning

confidence: 92%

Gαq-TRPC6-mediated Ca2+ Entry Induces RhoA Activation and Resultant Endothelial Cell Shape Change in Response to Thrombin

Singh

Knezevic

Ahmmed

et al. 2007

Journal of Biological Chemistry

202

215

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“…TRPC channels, including TRPC1, TRPC3, TRPC5, TRPC6, and TRPC7, are expressed in vascular smooth muscle cells and may contribute to I cat (2,12,28,36,39,40,54). In cerebral artery smooth muscle cells, TRPC3 channel knockdown attenuated endothelin-1-and IP 3 -induced [Ca 2ϩ ] i elevation and constriction, indicating that this isoform is a major contributor to the IP 3 R-induced I cat in this cell type (54).…”

Section: Discussionmentioning

confidence: 97%

Type 1 inositol 1,4,5-trisphosphate receptors mediate UTP-induced cation currents, Ca²⁺ signals, and vasoconstriction in cerebral arteries

Zhao

Adebiyi²,

Blaskova

et al. 2008

American Journal of Physiology-Cell Physiology

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,4,5-trisphosphate receptors (IP3Rs) regulate diverse physiological functions, including contraction and proliferation. There are three IP3R isoforms, but their functional significance in arterial smooth muscle cells is unclear. Here, we investigated relative expression and physiological functions of IP3R isoforms in cerebral artery smooth muscle cells. We show that 2-aminoethoxydiphenyl borate and xestospongin C, membrane-permeant IP3R blockers, reduced Ca 2ϩ wave activation and global intracellular Ca 2ϩ ([Ca 2ϩ ]i) elevation stimulated by UTP, a phospholipase C-coupled purinergic receptor agonist. Quantitative PCR, Western blotting, and immunofluorescence indicated that all three IP3R isoforms were expressed in acutely isolated cerebral artery smooth muscle cells, with IP3R1 being the most abundant isoform at 82% of total IP3R message. IP3R1 knockdown with short hairpin RNA (shRNA) did not alter baseline Ca 2ϩ wave frequency and global [Ca 2ϩ ]i but abolished UTP-induced Ca 2ϩ wave activation and reduced the UTP-induced global [Ca 2ϩ ]i elevation by ϳ61%. Antibodies targeting IP3R1 and IP3R1 knockdown reduced UTP-induced nonselective cation current (Icat) activation. IP3R1 knockdown also reduced UTP-induced vasoconstriction in pressurized arteries with both intact and depleted sarcoplasmic reticulum (SR) Ca 2ϩ by ϳ45%. These data indicate that IP 3R1 is the predominant IP3R isoform expressed in rat cerebral artery smooth muscle cells. IP 3R1 stimulation contributes to UTP-induced I cat activation, Ca 2ϩ wave generation, global [Ca 2ϩ ]i elevation, and vasoconstriction. In addition, IP 3R1 activation constricts cerebral arteries in the absence of SR Ca 2ϩ release by stimulating plasma membrane Icat.cerebral artery smooth muscle cells; calcium wave; short hairpin RNA INOSITOL 1,4,5-trisphosphate (IP 3 ) receptors (IP 3 Rs) are expressed in many cell types and regulate several physiological functions, including development, muscle contraction, cell proliferation, and differentiation (1,45,47,56 Rs (7,43,54). IP 3 also activates cation channels in vascular smooth muscle cells through mechanisms that do not require the stimulation of sarcoplasmic reticulum (SR) Ca 2ϩ release (27, 54). In cerebral artery smooth muscle cells, IP 3 R activation stimulates TRPC3 channels, leading to Na ϩ influx, membrane depolarization, voltage-dependent Ca 2ϩ channel activation, and vasoconstriction (54). Thus IP 3 Rs regulate ion channel activity, Ca 2ϩ signals, and physiological functions in the vasculature. However, despite the functional importance of IP 3 Rs in arterial smooth muscle cells, specific IP 3 R isoforms that are expressed in this cell type and their functional significance are poorly understood.Three IP 3 R isoforms, designated IP 3 R1, IP 3 R2, and IP 3 R3, are encoded by distinct genes (6, 37). IP 3 R isoform expression varies widely between different cell types. Cerebellar Purkinje neurons express predominantly IP 3 R1, pancreatic ␤-cells primarily express IP 3 R3, and cardiac myocytes express IP 3 R2 (14, 48...

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“…The closely related subgroup comprising TRPC3, TRPC6, and TRPC7 channels are directly activated by diacylglycerol through a PKC-independent mechanism (3,4). TRPC6 channels are highly expressed in a number of different tissues including vascular smooth muscle cells (5)(6)(7)(8). Despite their abundance, the exact physiological role of TRPC6 channels has not been elucidated.…”

mentioning

confidence: 99%

A common mechanism underlies stretch activation and receptor activation of TRPC6 channels

Spassova

Hewavitharana

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

438

353

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The TRP family of ion channels transduce an extensive range of chemical and physical signals. TRPC6 is a receptor-activated nonselective cation channel expressed widely in vascular smooth muscle and other cell types. We report here that TRPC6 is also a sensor of mechanically and osmotically induced membrane stretch. Pressure-induced activation of TRPC6 was independent of phospholipase C. The stretch responses were blocked by the tarantula peptide, GsMTx-4, known to specifically inhibit mechanosensitive channels by modifying the external lipid-channel boundary. The GsMTx-4 peptide also blocked the activation of TRPC6 channels by either receptor-induced PLC activation or by direct application of diacylglycerol. The effects of the peptide on both stretch-and diacylglycerol-mediated TRPC6 activation indicate that the mechanical and chemical lipid sensing by the channel has a common molecular mechanism that may involve lateral-lipid tension. The mechanosensing properties of TRPC6 channels highly expressed in smooth muscle cells are likely to play a key role in regulating myogenic tone in vascular tissue.GsMTx-4 peptide ͉ mechanosensitivity ͉ tarantula venom ͉ myogenic tone ͉ calcium signals T he superfamily of TRP cation channels transduce a remarkable spectrum of signals ranging from small secondmessenger molecules to physical parameters including temperature, osmolarity, and touch (1, 2). Among the several subfamilies of TRP channels, the TRPC nonselective cation channels activated in response to PLC-coupled receptors are widely expressed among tissues (2, 3). The closely related subgroup comprising TRPC3, TRPC6, and TRPC7 channels are directly activated by diacylglycerol through a PKC-independent mechanism (3, 4). TRPC6 channels are highly expressed in a number of different tissues including vascular smooth muscle cells (5-8). Despite their abundance, the exact physiological role of TRPC6 channels has not been elucidated. Recently it has been suggested that TRPC6 channels are involved in hemodynamic regulation (6, 9) and may play a role in generating myogenic tone in response to intravascular pressure in arteries (6, 9). This is a key mechanism to control blood flow in arteries and arterioles (10, 11) involving depolarization, activation of Ca 2ϩ entry, and the contraction of vascular smooth muscle cells (11). Increases in Ca 2ϩ in response to pressure not only activate smooth muscle cell contraction but also modify their growth and differentiation (12). However, the identity and gating mechanisms of the mechanical sensors that mediate the depolarizing response have not been identified.TRPC6 channels are expressed predominantly in cells responding to hydrostatic pressure changes including vascular smooth muscle and glomerular podocytes and have been implicated in mediating pressure-induced responses (6, 13). TRPC6 channels mediate receptor-induced depolarization in smooth muscle cells (7,9), and opening of the related TRPC1 channel has been shown to be activated by stretch (14). In addition to being implicated in ...

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

Cited by 132 publications

References 86 publications

Gαq-TRPC6-mediated Ca2+ Entry Induces RhoA Activation and Resultant Endothelial Cell Shape Change in Response to Thrombin

Gαq-TRPC6-mediated Ca2+ Entry Induces RhoA Activation and Resultant Endothelial Cell Shape Change in Response to Thrombin

Type 1 inositol 1,4,5-trisphosphate receptors mediate UTP-induced cation currents, Ca²⁺ signals, and vasoconstriction in cerebral arteries

A common mechanism underlies stretch activation and receptor activation of TRPC6 channels

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

Cited by 132 publications

References 86 publications

Gαq-TRPC6-mediated Ca2+ Entry Induces RhoA Activation and Resultant Endothelial Cell Shape Change in Response to Thrombin

Gαq-TRPC6-mediated Ca2+ Entry Induces RhoA Activation and Resultant Endothelial Cell Shape Change in Response to Thrombin

Type 1 inositol 1,4,5-trisphosphate receptors mediate UTP-induced cation currents, Ca2+ signals, and vasoconstriction in cerebral arteries

A common mechanism underlies stretch activation and receptor activation of TRPC6 channels

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Type 1 inositol 1,4,5-trisphosphate receptors mediate UTP-induced cation currents, Ca²⁺ signals, and vasoconstriction in cerebral arteries