期刊
CIRCULATION RESEARCH
卷 102, 期 11, 页码 1378-1388出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.107.167734
关键词
alpha(1)-adrenoceptor; L-type Ca2+; channel; G protein; PKC
We examined the effect of alpha(1)-adrenoceptor subtype-specific stimulation on L-type Ca2+ current (I-Ca) 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 alpha(1A)- and alpha(1B)-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 on I-Ca (transient decrease followed by sustained increase). However, selective alpha(1A)-adrenoceptor stimulation (>= 0.1 mu mol/L A61603) only potentiated I-Ca, and selective alpha(1B)-adrenoceptor stimulation (10 mu mol/L phenylephrine with 2 mu mol/L WB4101) only decreased I-Ca. The positive effect by alpha(1A)-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 alpha(1B)-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 PKC delta and epsilon to the T-tubules was observed only after alpha(1A)-adrenoceptor stimulation, but not after alpha(1B)-adrenoceptor stimulation. Immunoprecipitaion analysis revealed that alpha(1A)-adrenoceptor was associated with G(q/11), but alpha(1B)-adrenoceptor interacted with one of the pertussis toxin-sensitive G proteins, G(o). These findings demonstrated that the interactions of alpha(1B)-adrenoceptor subtypes with different G proteins elicit the formation of separate signaling cascades, which produce the opposite effects on I-Ca. The coupling of alpha(1A)-adrenoceptor with G(q/11)-PLC-PKC-CaMKII pathway potentiates I-Ca. In contrast, alpha(1B)-adrenoceptor interacts with G(o), of which the beta gamma-complex might directly inhibit the channel activity at T-tubules.
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