Open AccessAge attenuates the T‐type Ca V 3.2‐RyR axis in vascular smooth muscle
Author(s) -
Fan Gang,
Kaßmann Mario,
Cui Yingqiu,
Matthaeus Claudia,
Kunz Séverine,
Zhong Cheng,
Zhu Shuai,
Xie Yu,
Tsvetkov Dmitry,
Daumke Oliver,
Huang Yu,
Gollasch Maik
Publication year - 2020
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13134
Subject(s) - ryanodine receptor , thapsigargin , vascular smooth muscle , endocrinology , biology , medicine , trpc1 , mesenteric arteries , caveolae , extracellular , biophysics , receptor , endoplasmic reticulum , microbiology and biotechnology , transient receptor potential channel , biochemistry , signal transduction , smooth muscle , artery
Caveolae position Ca V 3.2 (T‐type Ca 2+ channel encoded by the α‐3.2 subunit) sufficiently close to RyR (ryanodine receptors) for extracellular Ca 2+ influx to trigger Ca 2+ sparks and large‐conductance Ca 2+ ‐activated K + channel feedback in vascular smooth muscle. We hypothesize that this mechanism of Ca 2+ spark generation is affected by age. Using smooth muscle cells (VSMCs) from mouse mesenteric arteries, we found that both Ca v 3.2 channel inhibition by Ni 2+ (50 µM) and caveolae disruption by methyl‐ß‐cyclodextrin or genetic abolition of Eps15 homology domain‐containing protein (EHD2) inhibited Ca 2+ sparks in cells from young (4 months) but not old (12 months) mice. In accordance, expression of Ca v 3.2 channel was higher in mesenteric arteries from young than old mice. Similar effects were observed for caveolae density. Using SMAKO Ca v 1.2 −/− mice, caffeine (RyR activator) and thapsigargin (Ca 2+ transport ATPase inhibitor), we found that sufficient SR Ca 2+ load is a prerequisite for the Ca V 3.2‐RyR axis to generate Ca 2+ sparks. We identified a fraction of Ca 2+ sparks in aged VSMCs, which is sensitive to the TRP channel blocker Gd 3+ (100 µM), but insensitive to Ca V 1.2 and Ca V 3.2 channel blockade. Our data demonstrate that the VSMC Ca V 3.2‐RyR axis is down‐regulated by aging. This defective Ca V 3.2‐RyR coupling is counterbalanced by a Gd 3+ sensitive Ca 2+ pathway providing compensatory Ca 2+ influx for triggering Ca 2+ sparks in aged VSMCs.