A novel catecholamine-activated adenosine cyclic 3',5'-phosphate independent pathway for beta-adrenergic receptor phosphorylation in wild-type and mutant S49 lymphoma cells: mechanism of homologous desensitization of adenylate cyclase.
A novel catecholamine-activated adenosine cyclic 3',5'-phosphate independent pathway for beta-adrenergic receptor phosphorylation in wild-type and mutant S49 lymphoma cells: mechanism of homologous desensitization of adenylate cyclase.
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野生型和突变型 S49 淋巴瘤细胞中儿茶酚胺激活的腺苷环 3,5-磷酸独立途径，用于 β-肾上腺素受体磷酸化：腺苷酸环化酶同源脱敏机制。
DOI：
10.1021/bi00354a027
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发表时间：
1986
期刊：
影响因子：
2.9
通讯作者：
Lefkowitz,RJ
中科院分区：
文献类型：
--
作者：
Strasser,RH;Sibley,DR;Lefkowitz,RJ
事实上，所有已知的由β-肾上腺素能受体和其它腺苷酸环化酶偶联受体刺激的生物学作用都是由cAMP依赖性蛋白激酶介导的。然而，“同源”或β-肾上腺素能激动剂特异性脱敏不需要cAMP。由于β-肾上腺素能受体磷酸化可能参与脱敏，我们研究了野生型S49淋巴瘤细胞（WT）和β-激动剂刺激的蛋白磷酸化的cAMP依赖性途径中有缺陷的两种突变体（眼睛不能响应β-肾上腺素能激动剂产生cAMP; kin缺乏cAMP依赖性激酶）中同源脱敏期间激动剂促进的受体磷酸化。所有三种细胞类型均显示出受体的快速、β-肾上腺素能激动剂促进的化学计量磷酸化，其显然不是cAMP介导的。磷酸化的氨基酸残基仅为丝氨酸。这些数据首次证明，儿茶酚胺可以通过cAMP非依赖性途径促进细胞蛋白（β-肾上腺素能受体）的磷酸化。此外，委员会认为，在腺苷酸环化酶-cAMP依赖性蛋白激酶途径中具有突变的细胞同源地使β-肾上腺素能受体脱敏和磷酸化的能力为受体磷酸化可能确实是脱敏的分子机制的中心的观点提供了非常强的支持。依赖性蛋白激酶（Krebs和Beavo，1979）。因此，已经显示关键的调节细胞蛋白在β-肾上腺素能激动剂刺激后变得磷酸化（Rubin和罗森，1985; Steinberg和Coffino，1979; Steinberg和Agard，1981; Nimmo，1998）。
Virtually all known biological actions stimulated by/3-adrenergicand other adenylate cyclase coupled receptors are mediated by cAMP-dependent protein kinase. Nonetheless,“homologous” or/3-ad-renergic agonist-specific desensitization does not require cAMP. Since/3-adrenergic receptor phosphorylation may be involved in desensitization, we studied agonist-promoted receptor phosphorylation during homologous desensitization in wild-type S49 lymphoma cells (WT) and two mutants defective in the cAMP-dependent pathway of/3-agonist-stimulated protein phosphorylation (eye" cannot generate cAMP in response to/3-adrenergic agonists; kin" lacks cAMP-dependent kinase). All three cell types demonstrate rapid,/3-adrenergic agonist-promoted, stoichiometric phosphorylation of the receptor which is clearly not cAMP mediated. The amino acid residue phosphorylated is solely serine. These data demonstrate, for the first time, that catecholamines can promote phosphorylation of a cellular protein (the/3-adrenergic receptor) via a cAMP-independent pathway. Moreover, the ability of cells with mutations in the adenylate cyclase-cAMP-dependent protein kinase pathway to both homologously desensitize and phosphorylate the/3-adrenergic receptors provides very strong support for the notion that receptor phosphorylation may indeed be central to the molecular mechanism of desensitization.Hormones that elevate intracellular levels of cAMP induce their physiological effects through phosphorylation of specific target proteins mediated by cAMP-dependent protein kinase (Krebs & Beavo, 1979). Accordingly, key regulatorycellular proteins have been shown to become phosphorylated upon/3-adrenergic agonist stimulation (Rubin & Rosen, 1985; Steinberg & Coffino, 1979; Steinberg & Agard, 1981; Nimmo