Role of receptor kinase in β1-adrenergic receptor signaling, and hypertrophy/heart failure

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Stimulation of α_1-adrenregic receptor (α_1AR) activates c-Jun NH_2-terminl kinase (JNK), a serine/threonine protein kinase, in rat neonatal myocytes. JNK belongs to a member of mitogen-activated protein kinase family, and is one of the key molecules mediating extracellular signal originating at cell surface to nucleus. In cardiomyocytes, stimulation of G protein-coupled receptors activates mitogen-activated protein kinases including JNK, and triggers hypertrophic responses. JNK activation is inhibited by the expression of carboxyl terminal regions of Gα_q, Gα_<12> and Gα_<13>. Involvement of Gα_q and Gα_<12/13> is further supported by the evidence that the JNK activation is inhibited by the expression of Gα_<q/11>-specific regulator of G protein signaling (RGS) domain of G protein-coupled receptor kinase 2 (GRK2) or Gα_<12/13>-specific RGS domain of p115-rhoGEF (p115-RGS). RGS domain contains 〜125 amino acids, and interacts with activated forms of specific Gα subunits. The expression of Gα_<q/11>- and Gα_i-specific RGS protein, RGS4, but not the treatment with PTX inhibits the JNK activation. Carboxyl terminal region of GRK2 that binds to Gβγ and blocks the function does not affect the JNK activation. These results suggest that Gα_<12/13> and Gα_q but not Gβγ mediate the α_1AR-induced JNK activation. The treatment of cells with EGTA, BAPTA-AM or nitrendipine almost completely inhibits the JNK activation. α_1AR stimulation slowly and gradually increases the intracellular Ca^<2+> that is sensitive to nitrendipine. This increase in the intracellular Ca^<2+> is also inhibited by the expression of p115-RGS, indicating the involvement of Gα_<12/13>. These results indicate that Gα_<12/13> activates JNK by the increased Ca^<2+> entry through L-type Ca^<2+> channel in rat neonatal myocytes.