Human CaV1.2/CaV3.x channels mediate paradoxical vasomotor responses in the human cerebral circulation (677.11)

Abstract

This study examined which voltage‐gated Ca2+ channels are expressed in the human cerebral circulation and investigated their electrical and functional properties. Using cerebral arteries collected from patients undergoing resection surgeries, quantitative PCR and Western blot analyses revealed the expression of both L‐ and T‐type channels in the smooth muscle cell layer. Analogous to rodent, we observed both CaV1.2 (L) and CaV3.2 (T); intriguingly, CaV3.1 isoform was replaced in humans with CaV3.3 (T). Patch‐clamp electrophysiology displayed a robust whole‐cell Ba2+ current whose amplitude varied inversely with the patients’ age. This inward current was subdivided into L‐ and T‐type components using standard pharmacological/electrical approaches. The T‐type conductance was further separated into CaV3.2 and CaV3.3 components by exploiting their differential sensitivity to Ni2+. Vessel myography revealed a key role for CaV1.2 and CaV3.3 channels in mediating cerebral arterial constriction with the former and latter predominating at depolarized and hyperpolarized voltages, respectively. Like the rodent, human CaV3.2 appears to drive a negative feedback response that antagonizes myogenic tone development. In conclusion, this study is the first to document three distinct Ca2+ channel isoforms in human cerebral arteries along with their unique contribution to arterial tone development.