Indirect coupling between Cav1.2 channels and ryanodine receptors to generate Ca2+ sparks in murine arterial smooth muscle cells.
In arterial vascular smooth muscle cells (VSMCs), Ca(2+) sparks stimulate nearby Ca(2+)-activated K(+) (BK) channels that hyperpolarize the membrane and close L-type Ca(2+) channels. We tested the contribution of L-type Ca(v)1.2 channels to Ca(2+) spark regulation in tibial and cerebral artery VSMCs using VSMC-specific Ca(v)1.2 channel gene disruption in (SMAKO) mice and an approach based on Poisson statistical analysis of activation frequency and first latency of elementary events. Ca(v)1.2 channel gene inactivation reduced Ca(2+) spark frequency and amplitude by approximately 50% and approximately 80%, respectively. These effects were associated with lower global cytosolic Ca(2+) levels and reduced sarcoplasmic reticulum (SR) Ca(2+) load. Elevating cytosolic Ca(2+) levels reversed the effects completely. The activation frequency and first latency of elementary events in both wild-type and SMAKO VSMCs weakly reflected the voltage dependency of L-type channels. This study provides evidence that local and tight coupling between the Ca(v)1.2 channels and ryanodine receptors (RyRs) is not required to initiate Ca(2+) sparks. Instead, Ca(v)1.2 channels contribute to global cytosolic [Ca(2+)], which in turn influences luminal SR calcium and thus Ca(2+) sparks.
Department of Nephrology and Medical Intensive Care, Charité Campus Virchow-Klinikum, Berlin, Germany.
Kirill
K
Essin
Andrea
A
Welling
Franz
F
Hofmann
Friedrich C
FC
Luft
Maik
M
Gollasch
Sven
S
Moosmang
D000818:Animals; D001488:Basilar Artery / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism*; D004095:Dihydropyridines; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D016909:Tibial Arteries / Q000378:metabolism
C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium