UNCOUPLING OF CARDIAC MUSCARINIC AND BETA-ADRENERGIC RECEPTORS FROM ION CHANNELS BY A GUANINE-NUCLEOTIDE ANALOG
UNCOUPLING OF CARDIAC MUSCARINIC AND BETA-ADRENERGIC RECEPTORS FROM ION CHANNELS BY A GUANINE-NUCLEOTIDE ANALOG
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DOI：
10.1038/317538a0
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发表时间：
1985-01-01
期刊：
影响因子：
64.8
通讯作者：
SZABO, G
中科院分区：
文献类型：
--
作者：
BREITWIESER, GE;SZABO, G
鸟嘌呤核苷酸结合蛋白，可互换地称为N或G蛋白，似乎是各种激动剂诱导的细胞膜功能的主要信号转导成分1 -3。在心脏中，G蛋白与β-肾上腺素能调节缓慢内向Ca 2+电流有关。我们研究了G蛋白在毒蕈碱激活乙酰胆碱（ACh）诱导的内向整流K+电流（IACh）和β-肾上腺素能激活异丙肾上腺素诱导的Ca ~（2+）电流（Isi）中的作用。在这里，我们报告了细胞内应用不可水解的GTP类似物5′-Guanylylimidodiophosphate（GppNHp）引起激动剂诱导的、拮抗剂抗性的、持续激活的IATlisi。这种通道与受体的功能性解偶联表明毒蕈碱受体和IAch通道是独立的分子结构。对毒蕈碱和β-肾上腺素能受体顺序激活的膜电导反应表明，与毒蕈碱抑制Isi相反，毒蕈碱刺激IAChis由G蛋白介导，通过不涉及腺苷酸环化酶的途径。总之，结果支持了激动剂是诱导GppNHp结合和/或G蛋白活化所必需的这一观点。一旦被激动剂触发，控制系统保持最大激活，从而转化细胞，使其不再响应随后的同源受体介导的信号。
Guanine nucleotide binding proteins, interchangeably called N or G proteins, seem to be tbe primary signal-transducing components of various agonist-induced cell membrane functions1–3. In the heart, G proteins have been implicated inβ-adrenergic modulation of the slow inward Ca2+current. We have investigated the role of G proteins in muscarinic activation of an inwardly rectifying, acetylcholine (ACh)-induced K+current (IACh), andβ-adrenergic activation of an (isoprenaline)-induced Ca2+current (Isi). Here we report that intracellular application of the non-hydrolysable GTP analogue 5′-guanylylimidodiphosphate (GppNHp) brought about an agonist-induced, antagonist-resistant, persistent activation ofIAChandIsi. This functional uncoupling of channel from receptor suggests that the muscarinic receptor and theIAchchannel are separate molecular structures. Membrane conductance responses to sequential activation of muscarinic andβ-adrenergic receptors demonstrate that in contrast to the muscarinic inhibition ofIsi, muscarinic stimulation ofIAChis mediated by a G protein via a pathway that does not involve adenylate cyclase. Taken together, the results support the notion that agonist is required to induce GppNHp binding and/or activation of the G proteins. Once triggered by agonist, the control system remains maximally activated, thereby transforming the cell so that it no longer responds to subsequent homologous receptor-mediated signals.