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Bitte verwenden Sie diesen Link, wenn Sie dieses Dokument zitieren oder verlinken wollen: https://nbn-resolving.org/urn:nbn:de:gbv:9-opus-41592

Age attenuates the T‐type CaV3.2‐RyR axis in vascular smooth muscle

  • Abstract Caveolae position CaV3.2 (T‐type Ca2+ channel encoded by the α‐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 Cav3.2 channel inhibition by Ni2+ (50 µM) 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 Cav3.2 channel was higher in mesenteric arteries from young than old mice. Similar effects were observed for caveolae density. Using SMAKO Cav1.2−/− mice, caffeine (RyR activator) and thapsigargin (Ca2+ transport ATPase inhibitor), we found that sufficient SR Ca2+ load is a prerequisite for the CaV3.2‐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 µM), but insensitive to CaV1.2 and CaV3.2 channel blockade. Our data demonstrate that the VSMC CaV3.2‐RyR axis is down‐regulated by aging. This defective CaV3.2‐RyR coupling is counterbalanced by a Gd3+ sensitive Ca2+ pathway providing compensatory Ca2+ influx for triggering Ca2+ sparks in aged VSMCs.

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Metadaten
Author: Gang Fan, Mario Kaßmann, Yingqiu Cui, Claudia Matthaeus, Séverine Kunz, Cheng Zhong, Shuai Zhu, Yu Xie, Dmitry Tsvetkov, Oliver Daumke, Yu Huang, Maik Gollasch
URN:urn:nbn:de:gbv:9-opus-41592
DOI:https://doi.org/10.1111/acel.13134
Parent Title (English):Aging Cell
Publisher:Wiley
Place of publication:Hoboken, New Jersey
Document Type:Article
Language:English
Date of first Publication:2020/04/29
Release Date:2021/02/06
Tag:T‐type calcium channels; aging; calcium sparks; caveolae; ryanodine receptors; vascular smooth muscle
GND Keyword:-
Volume:19
Issue:4
Faculties:Universitätsmedizin
Licence (German):License LogoCreative Commons - Namensnennung