ムスカリニック・レセプタ―の研究の展開 ―サブタイプ，サブグループを中心として―
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概要
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Since acetylcholine (ACh) was identified as a neurotransmitter at parasympathetic nerve terminals by pioneering pharmacologists such as O. Schmiedeberg, R. Hunt, O. Loewi and H.H. Dale, muscarinic acetylcholine receptors (mACh-R) serving as a transducer of muscarinic action have been assumed to exist. After many tries to identify the mACh-R, its existence was established by the group of S.H. Snyder, who employed binding assays with the radioligand <SUP>3</SUP>H-QNB. The presence of a neuronal (M<SUB>1</SUB>) and a peripheral (M<SUB>2</SUB>) mACh-R was suggested from the action of an M<SUB>1</SUB>-specific agonist, McN-A-343; and this observation was followed by the discovery that the antagonist pirenzepine had higher affinity for M<SUB>1</SUB> than for M<SUB>2</SUB>. Later, peripheral mACh-Rs were further subclassified in two types by the heart-specific action of gallamine and the different affinities of AF-DX116 and 4-DAMP. At present, three subtypes, M<SUB>1</SUB> (neuronal), M<SUB>2</SUB> (heart) and M<SUB>3</SUB> (other peripheral organs), can be pharmacologically distinguished by affinity differences. On the other hand, purification of mACh-R and analysis by gene technology revealed the presence of five mACh-R mRNAs (m1-m5), which were expressed in various organs with different abundances. These subtypes couple with subcellular muscarinic responses through different GTP-binding proteins. The connection between the subtypes, GTP-binding proteins and responses is not fully understood yet. Our studies showed that in guinea pig heart, in which only m2 mRNA is expressed, muscarinic agonists recognize two subgroups (M<SUB>2α</SUB> and M<SUB>2β</SUB>) with different affinities. One couples with the inhibition of adenylate cyclase, and the other couples with PI turnover through different GTP-binding proteins. These results indicate that the subtypes can be subclassified further with posttranslational protein modification.
- 社団法人 日本薬理学会の論文
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