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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Phosphorylation of serine 1928 in the distal C-terminal domain of cardiac Ca(v)1.2 channels during beta 1-adrenergic regulation
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Phosphorylation of serine 1928 in the distal C-terminal domain of cardiac Ca(v)1.2 channels during beta 1-adrenergic regulation

机译：β1肾上腺素调节期间心脏Ca（v）1.2通道的远端C末端域中丝氨酸1928的磷酸化

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During the fight-or-flight response, epinephrine and norepinephrine released by the sympathetic nervous system increase L-type calcium currents conducted by Ca(V)1.2a channels in the heart, which contributes to enhanced cardiac performance. Activation of beta-adrenergic receptors increases channel activity via phosphorylation by cAMP-dependent protein kinase (PKA) tethered to the distal C-terminal domain of the a, subunit via an A-kinase anchoring protein (AKAP15). Here we measure phosphorylation of S1928 in dissociated rat ventriculair myocytes in response to beta-adrenergic receptor stimulation by using a phosphospecific antibody. Isoproterenol treatment increased phosphorylation of S1928 in the distal C-terminal domain, and a similar increase was observed with a direct activator of adenylyl cyclase, forskolin, confirming that the cAMP and PKA are responsible. Pretreatment with selective beta 1-and beta 2-adrenergic antagonists reduced the increase in phosphorylation by 79% and 42%, respectively, and pretreatment with both agents completely blocked it. In contrast, treatment with these agents in the presence of 1,2-bis(2-aminophenoxy)ethane-N', N'-tetraacetic acid (BAPTA)-acetoxymethyl ester to buffer intracellular calcium results in only beta 1-stimulated phosphorylation of S1928. Whole-cell patch clamp studies with intracellular BAPTA demonstrated that 98% of the increase in calcium current was attributable to beta 1-adrenergic receptors. Thus, beta-adrenergic stimulation results in phosphorylation of S1928 on the Cav1.2 all subunit in intact ventricular myocytes via both beta 1- and beta 2-adrenergic receptor pathways, but the 132-dependent increase in phosphorylation depends on elevated intracellular calcium and does not contribute to regulation of whole-cell calcium currents at basal calcium levels. our results correlate phosphorylation of S1928 with beta 1-adrenergic functional up-regulation of cardiac calcium channels in the presence of BAPTA in intact ventricular myocytes.
机译：在战斗或逃跑反应期间，交感神经系统释放的肾上腺素和去甲肾上腺素会增加心脏中Ca（V）1.2a通道传导的L型钙电流，从而有助于增强心脏性能。 β-肾上腺素能受体的激活通过cAMP依赖性蛋白激酶（PKA）通过A激酶锚定蛋白（AKAP15）连接到a，亚基的远端C末端结构域的磷酸化来增加通道活性。在这里，我们测量解离的大鼠心室肌细胞中S1928的磷酸化，通过使用磷酸特异性抗体来响应β-肾上腺素能受体刺激。异丙肾上腺素治疗增加了远端C末端结构域中S1928的磷酸化，并且使用腺苷酸环化酶直接激活剂forskolin观察到了类似的增加，证实cAMP和PKA起作用。用选择性β1和β2肾上腺素能拮抗剂进行的预处理分别使磷酸化的增加减少了79％和42％，并且用这两种药物进行的预处理都将其完全阻断了。相反，在1,2-双（2-氨基苯氧基）乙烷-N'，N'-四乙酸（BAPTA）-乙酰氧基甲基酯存在下用这些试剂进行处理以缓冲细胞内钙离子仅会导致β1刺激磷酸化S1928。使用细胞内BAPTA进行全细胞膜片钳研究表明，钙电流增加的98％可归因于β1肾上腺素能受体。因此，β-肾上腺素刺激通过β1和β2肾上腺素能受体途径导致完整心室肌细胞Cav1.2所有亚基上的S1928磷酸化，但是132-依赖性磷酸化的增加取决于细胞内钙的升高，并且在基础钙水平上无助于调节全细胞钙电流。我们的研究结果表明，在完整的心室肌细胞中存在BAPTA的情况下，S1928的磷酸化与β1肾上腺素能心脏钙通道功能上调相关。

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