Venter J C, Kerlavage A R, Fraser C M
Biochem Soc Symp. 1986;52:1-22.
Purification and characterization of the neurotransmitter receptors of the autonomic nervous system have revealed considerable structural and functional homology between these pharmacologically distinct classes of information transduction molecules. Alpha 1- and alpha 2-adrenergic receptors are single polypeptides with molecular mass 85,000 Da and pI 4.6. Beta 1- and beta 2-adrenergic receptors are single polypeptides with molecular mass 68,000 Da and pI 5.0. Muscarinic cholinergic receptors from a variety of tissues and species are single polypeptides with molecular mass 80,000 Da and pI 4.2. Proteolytic digestion and analysis of affinity-labelled adrenergic and cholinergic receptors indicates a striking similarity in the number and sizes of peptides produced. Topographical analysis of the receptors has shown that they have a similar membrane orientation with more than half of the protein exposed to the extracellular environment. Peptide-mapping studies of soluble and membrane-bound receptors suggest that the ligand-binding domain of adrenergic and cholinergic receptors is localized near the end of the protein that is exposed to the extracellular environment. The marked similarity between alpha- and beta-adrenergic and muscarinic cholinergic receptor structure is perhaps not unexpected in light of the fact that these receptors interact with the same transmitters (in the case of alpha- and beta-adrenergic receptors) and/or with the same effector proteins in the membrane (stimulatory and inhibitory guanine nucleotide regulatory proteins, ion channels). Yet, depending on the tissue distribution of receptors and their effectors, this limited number of proteins can modulate dramatically different physiological effects. It may be that the differences in pharmacological specificity of ligand binding and the differences in receptor-effector interactions observed among adrenergic receptor subtypes and muscarinic cholinergic receptors are due to minor structural differences within the active sites of these proteins. Obviously, the real answers as to the extent of structural homology between the receptor classes will be derived from the amino acid sequencing of the purified proteins or from the cloning of the receptor genes and recently the genes coding for the beta-adrenergic receptor have been cloned and sequenced from human brain, hamster lung, and turkey erythrocytes. Comparison of the derived protein sequences reveals a high degree of structural homology between the avian and mammalian receptors with approximately 50% primary sequence identity and highly conserved secondary structure.(ABSTRACT TRUNCATED AT 400 WORDS)
自主神经系统神经递质受体的纯化与特性分析揭示了这些药理学上不同类别的信息转导分子之间存在相当程度的结构和功能同源性。α1和α2肾上腺素能受体是分子量为85,000道尔顿、等电点为4.6的单一多肽。β1和β2肾上腺素能受体是分子量为68,000道尔顿、等电点为5.0的单一多肽。来自多种组织和物种的毒蕈碱胆碱能受体是分子量为80,000道尔顿、等电点为4.2的单一多肽。对亲和标记的肾上腺素能和胆碱能受体进行蛋白水解消化和分析表明，所产生的肽段在数量和大小上具有显著相似性。对这些受体的拓扑分析表明，它们具有相似的膜取向，超过一半的蛋白质暴露于细胞外环境。对可溶性和膜结合受体的肽图谱研究表明，肾上腺素能和胆碱能受体的配体结合结构域位于蛋白质暴露于细胞外环境的末端附近。鉴于这些受体与相同的递质（就α和β肾上腺素能受体而言）和/或与膜中的相同效应蛋白（刺激性和抑制性鸟嘌呤核苷酸调节蛋白、离子通道）相互作用，α和β肾上腺素能受体与毒蕈碱胆碱能受体结构之间的显著相似性或许并不意外。然而，根据受体及其效应器的组织分布，这有限数量的蛋白质可调节截然不同的生理效应。肾上腺素能受体亚型和毒蕈碱胆碱能受体之间观察到的配体结合药理学特异性差异以及受体 - 效应器相互作用差异，可能是由于这些蛋白质活性位点内的微小结构差异所致。显然，关于受体类别之间结构同源程度的真正答案将来自纯化蛋白质的氨基酸测序或受体基因的克隆，最近已从人脑、仓鼠肺和火鸡红细胞中克隆并测序了编码β肾上腺素能受体的基因。对推导的蛋白质序列进行比较发现，禽类和哺乳动物受体之间存在高度的结构同源性，一级序列同一性约为50%，二级结构高度保守。（摘要截于400字）
