Figure 1.

Schema for β₁-AR–mediated cardiomyocyte stimulation and β₁-AR desensitization. The seven-membrane-spanning β₁-AR is stimulated by the physiologic agonist norepinephrine or by IgG specific for the receptor’s second extracellular loop (ECII) (in CHF subjects). The stimulated β₁-AR then activates the heterotrimeric G_s, which dissociates into its Gα_s* and Gβγ substituents. The Gα_s* activates both adenylyl cyclase (AC), which catalyzes cAMP formation, and the L-type calcium channel (L), which then permits Ca²⁺ to enter the cardiomyocyte. This Ca²⁺ can both augment contractility and, on a slower time scale, promote cardiomyocyte apoptosis by activating Ca²⁺/calmodulin kinase II (CaMK II). The cAMP produced by adenylyl cyclase activates PKA, which subsequently phosphorylates (P) numerous substrates important to sarcoplasmic [Ca²⁺] regulation: the L-type Ca²⁺ channel, the ryanodine receptor (RyR), and phospholamban (PLB). The net effect of this activity in the short term is to augment sarcoplasmic [Ca²⁺] and contractility. (In the long term, this activity engenders cardiomyocyte toxicity.) The activated β₁-AR is desensitized when it is phosphorylated by PKA (not shown) and by GRK2, the cellular expression of which increases with chronic β₁-AR stimulation. Translocation of GRK2 from the sarcoplasm to the sarcolemma requires Gβγ subunits, and this translocation is inhibited when GRK2ct is expressed heterologously in cardiomyocytes. Asterisks denote activated proteins.