中枢神経GABA<SUB>B</SUB>受容体の薬理
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概要
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Baclofen, a β-chlorophenyl derivative of γ-aminobutyric acid (GABA), depresses neuronal excitability in various parts of the central nervous system. The site of action for this drug had once been considered to be distinct from GABA recognition sites. In addition to the classical GABA recognition site (GABA<SUB>A</SUB> site), a new class of GABA receptor (GABA<SUB>B</SUB> site) has been characterized. GABA<SUB>B</SUB> sites are mainly present on nerve terminals and, when activated, result in diminished transmitter release, probably through a reduction in Ca<SUP>2+</SUP> influx. Baclofen was shown to be a selective agonist for this novel GABA<SUB>B</SUB> recognition. Baclofen also directly hyperpolarizes the membrane of mammalian brain neurons, in addition to its pretynaptic action. This postsynaptic action of baclofen was shown to result from an increase in K<SUP>+</SUP> conductance when studied in hippocampal pyramidal neurons through postsynaptic GABA<SUB>B</SUB> receptors. Thus, the inhibitory neurotransmitter GABA activates two receptor subtypes that can be distinguished by their physiological and pharmacological properties. GABA<SUB>A</SUB> receptors mediate rapid alterations in the distribution of Cl<SUP>-</SUP> across the membrane. GABA<SUB>A</SUB> receptors are linked directly to an ion channel, thus contributing to the prompt inhibition of cellular excitability. On the contrary, the GABA<SUB>B</SUB> receptor does not contain an integral ion channel and is thus responsible for slower responses through receptor-G-protein-effector complexes. G-protein may be directly coupled to K<SUP>+</SUP> or Ca<SUP>2+</SUP> channels. In addition, G-protein may modulate a variety of regulatory proteins or second messengers, thus contributing to the slower alteration of cellular excitability or to the modulation of neurotransmitter release.
- 社団法人 日本薬理学会の論文