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首页> 外文期刊>American Journal of Physiology >Differential coupling of beta3A- and beta3B-adrenergic receptors to endogenous and chimeric Galphas and Galphai.
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Differential coupling of beta3A- and beta3B-adrenergic receptors to endogenous and chimeric Galphas and Galphai.

机译：beta3A和beta3B肾上腺素受体与内源性和嵌合Galphas和Galphai的差异偶联。

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摘要

Chimeric G proteins made by replacing the COOH-terminal heptapeptide of G(alpha)q with the COOH-terminal heptapeptide of G(alpha)s or G(alpha)i were used to assess the relative coupling of beta(3)-adrenergic receptor (beta(3)-AR) splice variants (beta(3A) and beta(3B)) to G(alpha)s and G(alpha)i. The G(alpha)q/s and G(alpha)q/i chimeras transformed the response to receptor activation from regulation of adenylyl cyclase to mobilization of intracellular calcium (Ca(2+)(i)). Complementary high-throughput and single-cell approaches were used to evaluate agonist-induced coupling of the receptor to the G protein chimeras. In cells stably transformed with rat beta(3)-AR, transfected with the G protein chimeras, and evaluated using a scanning fluorometer, beta(3)-AR-induced coupling to G(alpha)q/s produced a rapid eightfold increase in Ca(2+)(i) followed by a slow decay to levels 25% above baseline. G(alpha)q/i also linked rat beta(3)-AR to mobilization of Ca(2+)(i) in a similar time- and agonist-dependent manner, but the net 2.5-fold increase in Ca(2+)(i) was only 30% of the response obtained with G(alpha)q/s. Activation of the rat beta(3)-AR also increased GTP binding to endogenous G(alpha)i threefold in membranes from CHO cells stably transformed with the receptor. A complementary single-cell imaging approach was used to assess the relative coupling of mouse beta(3A)- and beta(3B)-AR to G(alpha)i under conditions established to produce equivalent agonist-dependent coupling of the receptor splice variants to G(alpha)q/s and to increases in intracellular cAMP through endogenous G(alpha)s. The beta(3A)- and beta(3B)-AR coupled equivalently to G(alpha)q/i, but the temporal patterns of Ca(2+)(i) mobilization indicated that coupling was significantly less efficient than coupling to G(alpha)q/s. Collectively, these findings indicate less efficient but equivalent coupling of beta(3A)- and beta(3B)-AR to G(alpha)i vs. G(alpha)s and suggest that differential expression of the splice variants would not produce local differences in signaling networks linked to beta(3)-AR activation.
机译：通过用Gαs或Gαi的COOH末端七肽替换Gαq的COOH末端七肽制成的嵌合G蛋白用于评估β（3）-肾上腺素受体的相对偶联（β（3）-AR）剪接变体（beta（3A）和beta（3B））到Gαs和Gαi。 Gαq/ s和Gαq/ i嵌合体将对受体激活的响应从腺苷酸环化酶的调控转变为细胞内钙（Ca（2 +）（i））的动员。互补的高通量和单细胞方法用于评估激动剂诱导的受体与G蛋白嵌合体的偶联。在用大鼠beta（3）-AR稳定转化，用G蛋白嵌合体转染并使用扫描荧光计进行评估的细胞中，beta（3）-AR诱导的与Gαq/ s的偶联产生了快速的八倍增加Ca（2 +）（i）随后缓慢衰减至比基线高25％的水平。 G（alpha）q / i还以类似的时间和激动剂依赖性方式将大鼠beta（3）-AR与动员Ca（2 +）（i）相关联，但Ca（2+ ）（i）仅是Gαq/ s获得的响应的30％。大鼠beta（3）-AR的激活还增加了GTP与内源Gαi的结合，该结合是由被受体稳定转化的CHO细胞产生的膜的三倍。一种互补的单细胞成像方法用于评估在产生与受体剪接变体等效的激动剂依赖性偶联的条件下，小鼠β（3A）-和β（3B）-AR与Gαi的相对偶联。 Gαq/ s并通过内源性Gαs增加到细胞内cAMP中。 beta（3A）-和beta（3B）-AR与Gαq/ i等效耦合，但Ca（2 +）（i）动员的时间模式表明，耦合效率远低于与G（q alpha）q / s。总的来说，这些发现表明β（3A）-和β（3B）-AR与Gαi和Gα的耦合效率较低，但等效，并且表明剪接变体的差异表达不会产生局部差异在与beta（3）-AR激活链接的信令网络中。

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