Interaction of α1-Adrenoceptor Subtypes With Different G Proteins Induces Opposite Effects on Cardiac L-type Ca2+Channel

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Abstract
We examined the effect of α1-adrenoceptor subtype-specific stimulation on L-type Ca2+current (ICa) and elucidated the subtype-specific intracellular mechanisms for the regulation of L-type Ca2+channels in isolated rat ventricular myocytes. We confirmed the protein expression of α1A- and α1B-adrenoceptor subtypes at the transverse tubules (T-tubules) and found that simultaneous stimulation of these 2 receptor subtypes by nonsubtype selective agonist, phenylephrine, showed 2 opposite effects onICa(transient decrease followed by sustained increase). However, selective α1A-adrenoceptor stimulation (≥0.1 μmol/L A61603) only potentiatedICa, and selective α1B-adrenoceptor stimulation (10 μmol/L phenylephrine with 2 μ mol/L WB4101) only decreasedICa. The positive effect by α1A-adrenoceptor stimulation was blocked by the inhibition of phospholipase C (PLC), protein kinase C (PKC), or Ca2+/calmodulin-dependent protein kinase II (CaMKII). The negative effect by α1B-adrenoceptor stimulation disappeared after the treatment of pertussis toxin or by the prepulse depolarization, but was not attriburable to the inhibition of cAMP-dependent pathway. The translocation of PKCδ and ε to the T-tubules was observed only after α1A-adrenoceptor stimulation, but not after α1B-adrenoceptor stimulation. Immunoprecipitaion analysis revealed that α1A-adrenoceptor was associated with Gq/11, but α1B-adrenoceptor interacted with one of the pertussis toxin-sensitive G proteins, Go. These findings demonstrated that the interactions of α1-adrenoceptor subtypes with different G proteins elicit the formation of separate signaling cascades, which produce the opposite effects onICa. The coupling of α1A-adrenoceptor with Gq/11-PLC-PKC-CaMKII pathway potentiatesICa. In contrast, α1B-adrenoceptor interacts with Go, of which the βγ-complex might directly inhibit the channel activity at T-tubules.

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