E3-targeted anti-TRPC5 antibody inhibits store-operated calcium entry in freshly isolated pial arterioles

Xu, Shang‐Zhong; Boulay, Guylain; Flemming, R.; Beech, David J.

doi:10.1152/ajpheart.00495.2006

Cited by 80 publications

(88 citation statements)

References 57 publications

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“…Since there is a lack of selective pharmacological tools with which to study TRPC3 and TRPC6 function and RNA silencing proved ineffective in the CA smooth muscle, we evaluated the role of these channels in I UTP by inhibition with selective TRPC antibodies delivered via the patch pipette solution. This type of strategy has been used successfully by others to inhibit TRPC1, TRPC3, TRPC5, and TRPC6 channels (1,2,11,12,19,25). Surprisingly, we found significant inhibition of I UTP by intracellular incubation with anti-TRPC1 or anti-TRPC3 antibodies.…”

Section: Discussionmentioning

confidence: 71%

Inhibition of TRPC1/TRPC3 by PKG contributes to NO-mediated vasorelaxation

Chen¹,

Crossland²,

Noorani³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Nitric oxide (NO) inhibits transient receptor potential channel 3 (TRPC3) channels via a PKG-dependent mechanism. We sought to determine 1) whether NO inhibition of TRPC3 occurs in freshly isolated smooth muscle cells (SMC); and 2) whether NO inhibition of TRPC3 channels contributes to NO-mediated vasorelaxation. We tested these hypotheses in freshly isolated rat carotid artery (CA) SMC using patch clamp and in intact CA by vessel myograph. We demonstrated TRPC3 expression in whole CA (mRNA and protein) that was localized to the smooth muscle layers. TRPC1 protein was also expressed and coimmunoprecipitated with TRPC3. Whole cell patch clamp demonstrated nonselective cation channel currents that were activated by UTP (60 M) and completely inhibited by a TRPC channel inhibitor, La 3ϩ (100 M). The UTP-stimulated current (IUTP) was also inhibited by intracellular application of anti-TRPC3 or anti-TRPC1 antibody, but not by anti-TRPC6 or anti-TRPC4 control antibodies. We next evaluated the NO signaling pathway on I UTP. Exogenous NO [(Z)-1-{N-methyl-N-[6(N-methylammoniohexyl)-amino]}diazen-1-ium-1,2-diolate (MAHMA NONOate)] or a cellpermeable cGMP analog (8-bromo-cGMP) significantly inhibited I UTP . Preapplication of a PKG inhibitor (KT5823) reversed the inhibition of MAHMA NONOate or 8-bromo-cGMP, demonstrating the critical role of PKG in NO inhibition of TRPC1/TRPC3. Intact CA segments were contracted with UTP (100 M) in the presence or absence of La 3ϩ (100 M) and then evaluated for relaxation to an NO donor, sodium nitroprusside (1 nM to 1 M). Relaxation to sodium nitroprusside was significantly reduced in the La 3ϩ treatment group. We conclude that freshly isolated SMC express TRPC1/TRPC3 channels and that these channels are inhibited by NO/cGMP/PKG. Furthermore, NO contributes to vasorelaxation by inhibition of La 3ϩ -sensitive channels consistent with TRPC1/TRPC3. transient receptor potential channel; protein kinase G; transient receptor potential 3; transient receptor potential 1 THE CANONICAL TRANSIENT RECEPTOR potential channels (TRPCs) are nonselective cation channels that have been demonstrated to play a variety of roles in regulation of vascular tone (23). TRPC3 is one of the less well-characterized members of the TRPC family (TRPC1-7) within the vasculature. Nevertheless, TRPC3 has recently been shown to be involved in receptor-mediated constriction within the smooth muscle cells (SMCs) of cerebral arteries (18). Activation of the TRPC3 channel permits Ca 2ϩ and Na ϩ entry into the cell; however, the major mechanism of Ca 2ϩ entry in SMC is thought to be secondary to Na ϩ entry and smooth muscle depolarization (18). Depolarization from Na ϩ entry leads to activation of L-type Ca 2ϩ channels with subsequent Ca 2ϩ entry and smooth muscle contraction.Nitric oxide (NO) is well known as a vasodilator. However, the mechanism by which NO promotes smooth muscle relaxation is still incompletely resolved. At this time, it is believed that NO leads to smooth muscle relaxation by multiple pathways, including acti...

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Section: Discussionmentioning

confidence: 71%

Inhibition of TRPC1/TRPC3 by PKG contributes to NO-mediated vasorelaxation

Chen¹,

Crossland²,

Noorani³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…Moreover, TRPC4 knock-out strongly reduced acetylcholine-activated non-selective cation currents in visceral smooth muscle cells that are involved in the regulation of gastric motility (9). Similarly, functional expression of TRPC5 has been found in several vascular tissues, including human saphenous vein (10) and rabbit arteriolar smooth muscle cells (11). In addition, both TRPC4 and TRPC5 are strongly expressed in neuronal tissue and have been assigned functions in neurotransmitter release (12) and regulation of neurite growth, respectively (13,14).…”

Section: ؉mentioning

confidence: 91%

The Phospholipid-binding Protein SESTD1 Is a Novel Regulator of the Transient Receptor Potential Channels TRPC4 and TRPC5

Miehe

Bieberstein

Arnould

et al. 2010

Journal of Biological Chemistry

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TRPC4 and TRPC5 are two closely related members of the mammalian transient receptor potential cation channel family that have been implicated in important physiological functions, such as growth cone guidance and smooth muscle contraction. To further unravel the role of TRPC4 and TRPC5 in these processes in vivo, detailed information about the molecular composition of native channel complexes and their association with cellular signaling networks is needed. We therefore searched a human aortic cDNA library for novel TRPC4-interacting proteins using a modified yeast two-hybrid assay. This screen identified SESTD1, a previously uncharacterized protein containing a lipid-binding SEC14-like domain as well as spectrin-type cytoskeleton interaction domains. SESTD1 was found to associate with TRPC4 and TRPC5 via the channel's calmodulin-and inositol 1,4,5-trisphosphate receptor-binding domain. In functional studies, we demonstrate that SESTD1 binds several phospholipid species in vitro and is essential for efficient receptor-mediated activation of TRPC5. Notably, phospholipid binding to SESTD1 was Ca 2؉ -dependent. Because TRPC4 and -5 conduct Ca 2؉, SESTD1-channel signaling may be bidirectional and also couple TRPC activity to lipid signaling through SESTD1. The modulation of TRPC channel function by specific lipid-binding proteins, such as SESTD1, adds another facet to the complex regulation of these channels complementary to the previously described effects of direct channel-phospholipid interaction.Seven homologous channel proteins belong to the TRPC 3 family of nonselective cation channels. Within the TRPC family, TRPC4 and TRPC5 represent a structurally distinct subgroup that is characterized by its ability to form homo-and heteromultimeric channels with each other as well as with TRPC1 (1).Moreover, TRPC4 and TRPC5 are functionally set apart from other TRPCs by their unique activation mechanism that is dependent on phospholipase C activity but does not involve the phospholipid hydrolysis product diacylglycerol (2). Further signaling pathways, including Ca 2ϩ store depletion and diverse lipid-channel interactions, were also shown to control channel function (3-7). Nevertheless, the exact principles that govern TRPC4 and -5 gating have not been finally clarified and probably depend on the cellular context.Studies in knock-out mice showed that TRPC4 plays an important role in vascular physiology. TRPC4Ϫ/Ϫ mice have markedly reduced store-and receptor-induced endothelial Ca 2ϩ entry and impaired endothelium-dependent vasorelaxation (8). Moreover, TRPC4 knock-out strongly reduced acetylcholine-activated non-selective cation currents in visceral smooth muscle cells that are involved in the regulation of gastric motility (9). Similarly, functional expression of TRPC5 has been found in several vascular tissues, including human saphenous vein (10) and rabbit arteriolar smooth muscle cells (11). In addition, both TRPC4 and TRPC5 are strongly expressed in neuronal tissue and have been assigned functions in neurotransmitter...

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“…3C) (237). This SR-Ca 2ϩ release-independent mechanism is a major contributor to agonist-induced IP 3 R-mediated global [Ca 2ϩ ] i elevation and vasoconstriction in cerebral arteries (2,237 release may feedback to stimulate SOCE, which exists in some but not all contractile and migratory/proliferative SMC types (5,88,97,159,185,237,239). In addition to Orai and STIM proteins, TRP channels may be a molecular component of SOCE channels (73,180,229).…”

Section: Cellular Regulators Of Smc Ip 3 R Activitymentioning

confidence: 99%

Inositol trisphosphate receptors in smooth muscle cells

Narayanan

Adebiyi

Jaggar

2012

American Journal of Physiology-Heart and Circulatory Physiology

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Inositol 1,4,5-trisphosphate receptors (IP3Rs) are a family of tetrameric intracellular calcium (Ca2+) release channels that are located on the sarcoplasmic reticulum (SR) membrane of virtually all mammalian cell types, including smooth muscle cells (SMC). Here, we have reviewed literature investigating IP3R expression, cellular localization, tissue distribution, activity regulation, communication with ion channels and organelles, generation of Ca2+ signals, modulation of physiological functions, and alterations in pathologies in SMCs. Three IP3R isoforms have been identified, with relative expression and cellular localization of each contributing to signaling differences in diverse SMC types. Several endogenous ligands, kinases, proteins, and other modulators control SMC IP3R channel activity. SMC IP3Rs communicate with nearby ryanodine-sensitive Ca2+ channels and mitochondria to influence SR Ca2+ release and reactive oxygen species generation. IP3R-mediated Ca2+ release can stimulate plasma membrane-localized channels, including transient receptor potential (TRP) channels and store-operated Ca2+ channels. SMC IP3Rs also signal to other proteins via SR Ca2+ release-independent mechanisms through physical coupling to TRP channels and local communication with large-conductance Ca2+-activated potassium channels. IP3R-mediated Ca2+ release generates a wide variety of intracellular Ca2+ signals, which vary with respect to frequency, amplitude, spatial, and temporal properties. IP3R signaling controls multiple SMC functions, including contraction, gene expression, migration, and proliferation. IP3R expression and cellular signaling are altered in several SMC diseases, notably asthma, atherosclerosis, diabetes, and hypertension. In summary, IP3R-mediated pathways control diverse SMC physiological functions, with pathological alterations in IP3R signaling contributing to disease.

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E3-targeted anti-TRPC5 antibody inhibits store-operated calcium entry in freshly isolated pial arterioles

Cited by 80 publications

References 57 publications

Inhibition of TRPC1/TRPC3 by PKG contributes to NO-mediated vasorelaxation

Inhibition of TRPC1/TRPC3 by PKG contributes to NO-mediated vasorelaxation

The Phospholipid-binding Protein SESTD1 Is a Novel Regulator of the Transient Receptor Potential Channels TRPC4 and TRPC5

Inositol trisphosphate receptors in smooth muscle cells

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