Abstract

A human recombinant L-type Ca²⁺ channel (α_1C,77) was coexpressed with the rat angiotensin AT_1A receptor in Xenopus laevis oocytes. In oocytes expressing only α_1C,77 channels, application of human angiotensin II (1–10 μm) did not affect the amplitude or kinetics of Ba²⁺ currents (I_Ba). In sharp contrast, in oocytes coexpressing α_1C,77channels and AT_1A receptors, application of 1 nm to 1 μm angiotensin gradually and reversibly inhibited I_Ba, without significantly changing its kinetics. The inhibitory effect of angiotensin on I_Bawas abolished in oocytes that had been preincubated with losartan (an AT_1A receptor antagonist) or thapsigargin or injected with 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetate, pertussis toxin, guanosine-5′-O-(2-thio)diphosphate, or heparin, suggesting that the recombinant α_1C channels were regulated by angiotensin through G protein-coupled AT_1A receptors via activation of the inositol trisphosphate-dependent intracellular Ca²⁺ release pathway. Consistent with this hypothesis, no cross-signaling occurred between the AT_1A receptor and a splice variant of α_1Clacking Ca²⁺ sensors (α_1C,86). The data suggest that the regulation of recombinant L-type Ca²⁺channels by angiotensin is mediated by inositol trisphosphate-induced intracellular Ca²⁺ release and occurs at the molecular motif responsible for the Ca²⁺-induced inactivation of the channels.