Functional coupling of human L-type Ca2+ channels and angiotensin AT(1A) receptors coexpressed in Xenopus laevis oocytes: Involvement of the carboxyl-terminal Ca2+ sensors

A human recombinant L-type Ca2+ channel (alpha(1C,77)) was coexpressed with the rat angiotensin AT(1A) receptor in Xenopus laevis oocytes. In oocytes expressing only alpha(1C,77) channels, application of human angiotensin II (1-10 mu M) did not affect the amplitude or kinetics of Ba2+ currents (I-Ba ). In sharp contrast, in oocytes coexpressing alpha(1C,77) channels and AT( 1A) receptors, application of 1 nM to 1 mu M angiotensin gradually and reve rsibly inhibited I-Ba, without significantly changing its kinetics. The inh ibitory effect of angiotensin on I-Ba was abolished in oocytes that had bee n preincubated with losartan (an AT(1A) receptor antagonist) or thapsigargi n or injected with 1,2 -bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetate, p ertussis toxin, guanosine-5'-O-(2-thio)diphosphate, or heparin, suggesting that the recombinant alpha(1C) channels were regulated by angiotensin throu gh G protein-coupled AT(1A) receptors via activation of the inositol trisph osphate-dependent intracellular Ca2+ release pathway. Consistent with this hypothesis, no cross-signaling occurred between the AT(1A) receptor and a s plice variant of alpha(1C) lacking Ca2+ sensors (alpha(1C,86)). The data su ggest that the regulation of recombinant L-type Ca2+ channels by angiotensi n is mediated by inositol trisphosphate-induced intracellular Ca2+ release and occurs at the molecular motif responsible for the Ca2+-induced inactiva tion of the channels.