Differential targeting and signalling of voltage-gated T-type Ca(V) 3.2 and L-type Ca(V) 1.2 channels to ryanodine receptors in mesenteric arteries

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Item Type:	Article
Title:	Differential targeting and signalling of voltage-gated T-type Ca(V) 3.2 and L-type Ca(V) 1.2 channels to ryanodine receptors in mesenteric arteries
Creators Name:	Fan, G., Kaßmann, M., Hashad, A.M., Welsh, D.G. and Gollasch, M.
Abstract:	Recent data suggest that T-type Ca(V) 3.2 channels in arterial vascular smooth muscle cells (VSMCs) and pits structure of caveolae could contribute to elementary Ca(2+) signaling (Ca(2+) sparks) via ryanodine receptors (RyRs) to cause vasodilation. While plausible, their precise involvement in igniting Ca(2+) sparks remain largely unexplored. The goal of this study was to elucidate the contribution of caveolar Ca(V) 3.2 channels and their functional interaction with Ca(V) 1.2 channels to trigger Ca(2+) sparks in VSMCs from mesenteric, tibial and cerebral arteries. We used tamoxifen-inducible smooth muscle-specific Ca(V) 1.2(-/-) (SMAKO) mice and laser scanning confocal microscopy to assess Ca(2+) spark generation in VSMCs. Ni(2+), Cd(2+) and methyl-ß-cyclodextrin were used to inhibit Ca(V) 3.2 channels, Ca(V) 1.2 channels, and caveolae, respectively. Ni(2+) (50 μmol/L) and methyl-ß-cyclodextrin (10 mmol/L) decreased Ca(2+) spark frequency by ∼20-30% in mesenteric VSMCs in a non-additive manner, but failed to inhibit Ca(2+) sparks in tibial and cerebral artery VSMCs. Cd(2+) (200 μmol/L) suppressed Ca(2+) sparks in mesenteric arteries by ∼70-80%. A similar suppression of Ca(2+) sparks was seen in mesenteric artery VSMCs of SMAKO mice. The remaining Ca(2+) sparks were fully abolished by Ni(2+) or methyl-ß-cyclodextrin. Our data demonstrate that Ca2+ influx through Ca(V) 1.2 channels is the primary means of triggering Ca(2+) sparks in murine arterial VSMCs. Ca(V) 3.2 channels, localized to caveolae and tightly coupled to RyR, provide an additional Ca(2+) source for Ca(2+) spark generation in mesenteric, but not tibial and cerebral arteries.
Keywords:	Ryanodine Receptors, Calcium Sparks, T-Type Calcium Channels, L-Type Calcium Channels, BK(Ca) Channels, Blood Pressure, Animals, Mice
Source:	Journal of Physiology
ISSN:	0022-3751
Publisher:	Wiley
Volume:	596
Number:	20
Page Range:	4863-4877
Date:	15 October 2018
Official Publication:	https://doi.org/10.1113/JP276923
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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