Coupling of β1-adrenergic receptor to type 5 adenylyl cyclase and its physiological relevance in cardiac myocytes

Abstract Myocardial β-adrenergic receptor (β-AR) β 1 - and β 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): β 1 -AR and AC5 promote cardiac remodeling, while β 2 -AR and AC6 activate cell survival pathways. However, the mechanisms involved remain poorly understood. We hypothesized that AC5 is coupled preferentially to β 1 -AR rather than β 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 β 1 -AR stimulation, but had no effect on cAMP accumulation and cardiac apoptosis in response to selective β 2 -AR stimulation. The results of selective stimulation of β 1 -AR and β 2 -AR in neonatal cardiac myocytes prepared from wild-type and AC5-knockout mice were also consistent with the idea that β 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.