Coupling of β-adrenergic receptors to cardiac L-type Ca2+ channels:: Preferential coupling of the β1 versus β2 receptor subtype and evidence for PKA-independent activation of the channel

beta 1- and beta 2-adrenergic receptors (beta-ARs) co-exist in mammalian heart, and it is generally accepted that both activate adenylyl cyclase (AC), resulting in increased levels of cAMP and subsequent activation of L-type Ca2+ channels (CaCh). To investigate the contribution of each beta-AR subtype in AC and CaCh coupling, we stably expressed cardiac CaCh alpha 1 and beta 2 subunits along with either beta 1-AR or beta 2-AR in CHW fibroblasts. Go-expression of either P-AR with CaCh subunits conferred responsiveness of AC and CaCh to isoproterenol (ISO), which was not observed in non-transfected cells. ISO-promoted cAMP formation occurred at a lower EC50 through the beta 2-AR than through the beta 1-AR (0.13 +/- 0.01 vs. 0.6 +/- 0.14 nM). In contrast, activation of CaCh was more efficacious via the beta 1-AR than the beta 2-AR (EC50 for CaCh activation = 238 +/- 33 vs. 1057 +/- 113 nM). Pre-treatment with pertussis toxin (PTX) had no effect upon the responsiveness of either cAMP formation or CaCh activation through either receptor. We conclude (1) that beta 1-ARs exhibit preferential coupling to CaCh activation, versus that observed for the beta 2-AR; (2) that this preferential coupling cannot be explained solely by cAMP-dependent processes; and (3) that the relative attenuation of beta 2-AR-promoted CaCh activation is not due to receptor coupling to PTX-sensitive G proteins. Thus, it is likely that other subtype-specific, cAMP-independent coupling of the beta-AR to CaCh is present. CELL SIGNAL 11;5:337-342, 1999. (C) 1999 Elsevier Science Inc.