Differential regulation of transient receptor potential melastatin 6 and 7 cation channels by ANG II in vascular smooth muscle cells from spontaneously hypertensive rats

2006 ◽  
Vol 290 (1) ◽  
pp. R73-R78 ◽  
Author(s):  
Rhian M. Touyz ◽  
Ying He ◽  
Augusto C. I. Montezano ◽  
Guoying Yao ◽  
Vladimir Chubanov ◽  
...  
Keyword(s):  
Spontaneously Hypertensive Rats ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cation Channels ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Annexin 1 ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

Intracellular Mg2+ depletion has been implicated in vascular dysfunction in hypertension. We demonstrated that transient receptor potential melastatin 7 (TRPM7) cation channels mediate Mg2+ influx in VSMCs. Whether this plays a role in [Mg2+]i deficiency in hypertension is unclear. Here, we tested the hypothesis that downregulation of TRPM7 and its homologue TRPM6 is associated with reduced [Mg2+]i and that ANG II negatively regulates TRPM6/7 in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR). Cultured VSMCs from Wistar Kyoto (WKY) and SHR were studied. mRNA and protein expression of TRPM6 and TRPM7 were assessed by RT-PCR and immunoblotting, respectively. Translocation of annexin-1, specific TRPM7 substrate, was measured as an index of TRPM7 activation. [Mg2+]i was determined using mag fura-2. VSMCs from WKY and SHR express TRPM6 and TRPM7. Basal TRPM6 expression was similar in WKY and SHR, but basal TRPM7 content was lower in VSMCs from SHR vs. WKY. This was associated with significantly reduced [Mg2+]i in SHR cells ( P < 0.01). ANG II time-dependently increased TRPM6 expression, with similar responses in WKY and SHR. ANG II significantly increased TRPM7 expression in WKY ( P < 0.05), but not in SHR. Annexin-1 translocation was reduced 1.5–2-fold in SHR vs. WKY. Our findings demonstrate that TRPM6 and TRPM7 are differentially regulated in VSMCs from SHR and WKY. Whereas TRPM6 is unaltered in SHR, expression of TRPM7 is blunted. This was associated with attenuated annexin-1 translocation and decreased VSMC [Mg2+]i in SHR. Downregulation of TRPM7, but not TRPM6, may play a role in altered Mg2+ homeostasis in VSMCs from SHR.

scholarly journals Upregulation of Transient Receptor Potential Canonical Type 3 Channel via AT1R/TGF-β1/Smad2/3 Induces Atrial Fibrosis in Aging and Spontaneously Hypertensive Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Rongfang He ◽  
Juan Zhang ◽  
Dan Luo ◽  
Yiyan Yu ◽  
Tangting Chen ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Neonatal Rat ◽  
Ang Ii ◽  
Atrial Fibrosis ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Collagen Iii ◽  
Transient Receptor ◽  
O 24

Fibroblast proliferation and migration are central in atrial fibrillation (AF) promoting structure remodeling, which is strongly associated with aging and hypertension. Transient receptor potential canonical-3 channel (TRPC3) is a key mediator of cardiac fibrosis and the pathogenesis of AF. Here, we have observed the increased TRPC3 expression that induced atrial fibrosis which possibly is either mediated by the aging process or related to hypertensive progression. In this study, we measured the pathological structure remodeling by H&E staining, Masson staining, and transmission electron microscope (TEM). The protein expression levels of fibrotic biomarkers and TRPC3 were measured by Western blotting with atrial tissues from normotensive Wistar Kyoto rats (WKY 4m-o (4 months old)), old WKY (WKY 24m-o (24 months old)), spontaneously hypertensive rat (SHR 4m-o (4 months old)), and old SHR (SHR 24m-o (24 months old)). To illuminate the molecular mechanism of TRPC3 in atrial fibrosis of aging rats and SHR, we detected the inhibited role of TRPC3 selective blocker ethyl-1-(4-(2,3,3-trichloroacrylamide) phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate,pyrazole-3 (Pyr3) on angiotensin II (Ang II) induced fibrosis in neonatal rat atrial fibroblasts. The pathological examination showed that the extracellular matrix (ECM) and collagen fibrils were markedly increased in atrial tissues from aged and hypertensive rats. The protein expressions of fibrotic biomarkers (collagen I, collagen III, and transforming growth factor-β1 (TGF-β1)) were significantly upregulated in atrial tissues from the WKY 24m-o group, SHR 4m-o group, and SHR 24m-o group compared with the WKY 4m-o group. Meanwhile, the expression level of TRPC3 was significantly upregulated in WKY 24m-o and SHR 4m-o atrial tissues compared to WKY 4m-o rats. In isolated and cultured neonatal rat atrial fibroblasts, Ang II induced the atrial fibroblast migration and proliferation and upregulated the expression levels of TRPC3 and fibrotic biomarkers. TRPC3 selected blocker Pyr3 attenuated the migration and proliferation in neonatal rat atrial fibroblasts. Furthermore, Pyr3 significantly alleviated Ang II-induced upregulation of TRPC3, collagen I, collagen III, and TGF-β1 through the molecular mechanism of the TGF-β/Smad2/3 signaling pathway. Similarly, knocking down TRPC3 using short hairpin RNA (shTRPC3) also attenuated Ang II-induced upregulation of TGF-β1. Pyr3 preconditioning decreased Ang II-induced intracellular Ca2+ transient amplitude elevation. Furthermore, AT1 receptor was involved in Ang II-induced TRPC3 upregulation. Hence, upregulation of TRPC3 in aging and hypertension is involved in an atrial fibrosis process. Inhibition of TRPC3 contributes to reverse Ang II-induced fibrosis. TRPC3 may be a potential therapeutic target for preventing fibrosis in aging and hypertension.

Abstract P219: Vascular Cross-talk Between Redox and Calcium Signaling in Hypertension Involves Transient Receptor Potential Melastatin 2 Channel Activation

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Rhéure Alves-Lopes ◽  
Augusto C Montezano ◽  
Karla B Neves ◽  
Aikaterini Anagnostopoulou ◽  
Silvia Lacchini ◽  
...  
Keyword(s):  
Cross Talk ◽  
Transient Receptor Potential ◽  
Vascular Dysfunction ◽  
Receptor Potential ◽  
Mesenteric Arteries ◽  
Ang Ii ◽  
Channel Activation ◽  
Hypertensive Patients ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

The transient receptor potential melastatin 2 cation channel (TRPM2) is redox-sensitive and promotes Ca 2+ influx after H 2 O 2 activation through oxidative modification and PARP-ADPR-dependent mechanisms. TRPM2 also regulates Na + influx, and by increasing [Na + ]i interferes with the Na + -Ca 2+ exchanger (NCX) inducing reverse mode action, promoting Ca 2+ influx. These processes may be driven by Nox4-derived H 2 O 2. We tested the hypothesis that vascular dysfunction in hypertension involves oxidative stress-induced TRPM2 activation through H 2 O 2 production, which in turn promotes Ca 2+ influx. Mesenteric arteries isolated from wildtype (WT), LinA3 (mice expressing human renin with Ang II-dependent hypertension), Nox4 -/- and LinA3/Nox4 -/- mice and vascular smooth muscle cells (VSMCs) from hypertensive and normotensive patients were used. Arteries from hypertensive LinA3 mice, exhibit increased U46619-induced vasoconstriction versus WT mice (Emax - LinA3 vs WT: 9.37 ± 0.51 vs 6.79 ± 0.29), an effect attenuated by olaparib (PARP-ADPR inhibitor) and 2-APB (TRPM2 blocker) and also increased mRNA expression (Fold change - related to control) of NOX4 (3.05 ± 0.30), TRPM2 (1.38 ± 0.24), NCX (1.973 ± 0.34) and salt inducible kinase 1 (1.833 ± 0.12) and sodium-potassium pump (1.43 ± 0.16), which are activated when intracellular levels of Na + rise beyond a critical point. These events seem to be regulated by NOX4, since they were not observed in mesenteric arteries from LinA3/Nox4 -/- mice. Ang II-induced Ca 2+ influx is potentiated in VSMCs from hypertensive patients (AUC-Ex490/Em535: normotensive: 15400±917.5 vs hypertensive - 22460±2388), a response followed by increased generation of O 2 - and H 2 O 2 in cells from hypertensive patients. These ROS effects were attenuated by catalase, and 2-APB, 8-br and olaparib (TRPM2 inhibitors) and benzamil, KB-R7943 and YM244769 (NCX inhibitors). Our data indicate that TRPM2 ion channel activation contributes to redox-sensitive vascular dysfunction in hypertension. These findings suggest that dysregulation of TRPM2-NOX4-derived ROS and NCX may contribute to redox- and Ca 2+ signalling important in vascular function in hypertension. TRPM2 may be a point of cross-talk between ROS and Ca 2+ signalling.

scholarly journals Drosophila menthol sensitivity and the Precambrian origins of transient receptor potential-dependent chemosensation

2019 ◽  
Vol 374 (1785) ◽  
pp. 20190369 ◽  
Author(s):  
Nathaniel J. Himmel ◽  
Jamin M. Letcher ◽  
Akira Sakurai ◽  
Thomas R. Gray ◽  
Maggie N. Benson ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Cation Channels ◽  
Transient Receptor Potential Melastatin ◽  
Growing Body ◽  
Sensitivity Studies ◽  
Transient Receptor ◽  
Class Iv

Transient receptor potential (TRP) cation channels are highly conserved, polymodal sensors which respond to a wide variety of stimuli. Perhaps most notably, TRP channels serve critical functions in nociception and pain. A growing body of evidence suggests that transient receptor potential melastatin (TRPM) and transient receptor potential ankyrin (TRPA) thermal and electrophile sensitivities predate the protostome–deuterostome split (greater than 550 Ma). However, TRPM and TRPA channels are also thought to detect modified terpenes (e.g. menthol). Although terpenoids like menthol are thought to be aversive and/or harmful to insects, mechanistic sensitivity studies have been largely restricted to chordates. Furthermore, it is unknown if TRP-menthol sensing is as ancient as thermal and/or electrophile sensitivity. Combining genetic, optical, electrophysiological, behavioural and phylogenetic approaches, we tested the hypothesis that insect TRP channels play a conserved role in menthol sensing. We found that topical application of menthol to Drosophila melanogaster larvae elicits a Trpm - and TrpA1 -dependent nocifensive rolling behaviour, which requires activation of Class IV nociceptor neurons. Further, in characterizing the evolution of TRP channels, we put forth the hypotheses that three previously undescribed TRPM channel clades (basal, αTRPM and βTRPM), as well as TRPs with residues critical for menthol sensing, were present in ancestral bilaterians. This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.

scholarly journals Nitric oxide signals through IRAG to inhibit TRPM4 channels and dilate cerebral arteries

Function ◽  
2021 ◽  
Author(s):  
Sher Ali ◽  
Alfredo Sanchez Solano ◽  
Albert L Gonzales ◽  
Pratish Thakore ◽  
Vivek Krishnan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Sarcoplasmic Reticulum ◽  
Smooth Muscle Cells ◽  
Blood Vessels ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cation Channels ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

Abstract Nitric oxide (NO) relaxes vascular smooth muscle cells (SMCs) and dilates blood vessels by increasing intracellular levels of cyclic guanosine monophosphate (cGMP), which stimulates the activity of cGMP-dependent protein kinase (PKG). However, the vasodilator mechanisms downstream of PKG remain incompletely understood. Here, we found that transient receptor potential melastatin 4 (TRPM4) cation channels, which are activated by Ca2+ released from the sarcoplasmic reticulum (SR) through inositol triphosphate receptors (IP3Rs) under native conditions, are essential for SMC membrane depolarization and vasoconstriction. We hypothesized that signaling via the NO/cGMP/PKG pathway causes vasodilation by inhibiting TRPM4. We found that TRPM4 currents activated by stretching the plasma membrane or directly activating IP3Rs were suppressed by exogenous NO or a membrane-permeable cGMP analog, the latter of which also impaired IP3R-mediated release of Ca2+ from the SR. The effects of NO on TRPM4 activity were blocked by inhibition of soluble guanylyl cyclase or PKG. Notably, upon phosphorylation by PKG, IRAG (IP3R-associated PKG substrate) inhibited IP3R-mediated Ca2+ release, and knockdown of IRAG expression diminished NO-mediated inhibition of TRPM4 activity and vasodilation. Using superresolution microscopy, we found that IRAG, PKG, and IP3Rs form a nanoscale signaling complex on the SR of SMCs. We conclude that NO/cGMP/PKG signaling through IRAG inhibits IP3R-dependent activation of TRPM4 channels in SMCs to dilate arteries. Significance Statement: Nitric oxide (NO) is a gaseous vasodilator produced by endothelial cells that is essential for cardiovascular function. Although NO-mediated signaling pathways have been intensively studied, the mechanisms by which they relax smooth muscle cells (SMCs) to dilate blood vessels remain incompletely understood. In this study, we show that NO causes vasodilation by inhibiting the activity of Ca2+-dependent TRPM4 (transient receptor potential melastatin 4) cation channels. Probing further, we found that NO does not act directly on TRPM4 but instead initiates a signaling cascade that inhibits its activation by blocking the release of Ca2+ from the sarcoplasmic reticulum. Thus, our findings reveal the essential molecular pathways of NO-induced vasodilation—a fundamental unresolved concept in cardiovascular physiology.

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