Age attenuates the T-type Ca(V)3.2-RyR axis in vascular smooth muscle
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AbstractCaveolae position Ca(V)3.2 (T-type Ca2+ channel encoded by the alpha-3.2 subunit) sufficiently close to RyR (ryanodine receptors) for extracellular Ca2+ influx to trigger Ca2+ sparks and large-conductance Ca2+-activated K+ channel feedback in vascular smooth muscle. We hypothesize that this mechanism of Ca2+ 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 Ni2+ (50 mu M) and caveolae disruption by methyl-ss-cyclodextrin or genetic abolition of Eps15 homology domain-containing protein (EHD2) inhibited Ca2+ 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 (Ca2+ transport ATPase inhibitor), we found that sufficient SR Ca2+ load is a prerequisite for the Ca(V)3.2-RyR axis to generate Ca2+ sparks. We identified a fraction of Ca2+ sparks in aged VSMCs, which is sensitive to the TRP channel blocker Gd3+ (100 mu M), 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 Gd3+ sensitive Ca2+ pathway providing compensatory Ca2+ influx for triggering Ca2+ sparks in aged VSMCs.
All Author(s) ListGang FAN, Mario KAßMANN, Yingqiu CUI, Claudia MATTHAEUS, Séverine KUNZ, Cheng ZHONG, Shuai ZHU, Yu XIE, Dmitry TSVETKOV, Oliver DAUMKE, Yu HUANG, Maik GOLLASCH
Journal nameAging Cell
Detailed descriptionCorresponding author: Maik Gollasch; Original Article
Volume Number19
Issue Number4
Article numbere13134
LanguagesEnglish-United Kingdom
Keywordsaging, calcium sparks, caveolae, ryanodine receptors, T-type calcium channels, vascular smooth muscle
Web of Science Subject CategoriesCell Biology;Geriatrics & Gerontology;Cell Biology;Geriatrics & Gerontology

Last updated on 2021-20-01 at 00:04