Knockout of adenylyl cyclase isoform 5 or 6 differentially modifies the β-adrenoceptor-mediated inotropic response.

Although only β-adrenergic receptors (βAR) dually couple with stimulatory G protein (G) and inhibitory G protein (G), inactivation of G enhances both βAR and βAR responsiveness. We hypothesize that G restrains spontaneous adenylyl cyclase (AC) activity independent of receptor activation. Subcellular localization of the AC5/6 subtypes varies contributing to the compartmentation of βAR signaling.