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―

抄録

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, it's existence was established by the group of S.H. Snyder, who employed binding assays with the radioligand ³H-QNB. The presence of a neuronal (M₁) and a peripheral (M₂) mACh-R was suggested from the action of an M₁-specific agonist, McN-A-343; and this observation was followed by the discovery that the antagonist pirenzepine had higher affinity for M₁ than for M₂. 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, M₁ (neuronal), M₂ (heart) and M₃ (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_2α and M_2β) 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.