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

α_1肾上腺素受体（α_1-adrenregic receptor, α_1- ar）在大鼠新生肌细胞中激活c-Jun NH_2-terminl kinase (JNK)，这是一种丝氨酸/苏氨酸蛋白激酶。JNK属于丝裂原活化蛋白激酶家族成员，是介导细胞表面到细胞核的胞外信号的关键分子之一。在心肌细胞中，G蛋白偶联受体的刺激可激活丝裂原活化的蛋白激酶，包括JNK，并引发肥厚反应。Gα_q、Gα_<12>和Gα_<13>的羧基末端区域的表达抑制了JNK的激活。Gα_q和Gα_<12/13>的参与进一步被Gα_<q/11>特异性调节G蛋白信号传导（RGS）域的G蛋白偶联受体激酶2 （GRK2）或Gα_<12/13>特异性RGS域的p115-rhoGEF （p115-RGS）的表达抑制JNK激活的证据所支持。RGS结构域包含约125个氨基酸，并与特定Gα亚基的活化形式相互作用。Gα_<q/11>-和g α_i特异性RGS蛋白RGS4的表达抑制JNK的激活，而PTX不抑制。GRK2的羧基末端区域与Gβγ结合并阻断其功能，不影响JNK的激活。上述结果表明，Gα_<12/13>和Gα_q介导了α _1ar诱导的JNK活化，而Gβγ介导不了。用EGTA、BAPTA-AM或尼群地平处理细胞几乎完全抑制JNK的激活。α_1AR刺激缓慢而逐渐增加细胞内对尼群地平敏感的Ca^<2+>。细胞内Ca^<2+>的增加也被p115-RGS的表达所抑制，表明Gα_<12/13>的参与。这些结果表明，Gα_<12/13>通过l型Ca^<2+>通道增加Ca^<2+>进入大鼠新生肌细胞，从而激活JNK。

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.