Myocardial beta-adrenergic receptor (beta-AR) beta(1)- and beta(2)-subtypes are highly homologous, but play opposite roles in cardiac apoptosis and heart failure, as do cardiac adenylyl cyclase (AC) subtypes 5 (AC5) and 6 (AC6): beta(1)-AR and AC5 promote cardiac remodeling, while beta(2)-AR and AC6 activate cell survival pathways. However, the mechanisms involved remain poorly understood. We hypothesized that AC5 is coupled preferentially to beta(1)-AR rather than beta(2)-AR, and we examined this idea by means of pharmacological and genetic approaches. We found that selective inhibition of AC5 with 2'5'-dideoxyadenosine significantly suppressed CAMP accumulation and cardiac apoptosis induced by selective beta(1)-AR stimulation, but had no effect on cAMP accumulation and cardiac apoptosis in response to selective beta(2)-AR stimulation. The results of selective stimulation of beta(1)-AR and beta(2)-AR in neonatal cardiac myocytes prepared from wild-type and AC5-knockout mice were also consistent with the idea that beta(1)-AR selectively couples with AC5. We believe these results are helpful for understanding the mechanisms underlying the different roles of AR subtypes in healthy and diseased hearts. (C) 2015 Elsevier Inc. All rights reserved.