| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1999: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1998: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
GABA (γ-aminobutyric acid) is the major inhibitory neurotransmitter in the central nervous system and is also present in several peripheral tissues, where it could have a functional role in the regulation of muscle contraction or hormonal secretion. The receptors for GABA are pharmacologically classified into two major subtypes, ionotropic GABAA and metabotropic GABAB receptors. The GABAA receptor is the target of several centrally active drugs, including barbiturates and benzodiazepines, and responds to the antagonist bicuculline. Activation of the GABAA receptor results in opening of a chloride channel and hyperpolarization of postsynaptic cells. The GABAB receptor is operationally defined by selective activation by baclofen and thc lack of sensitivity towards bicuculline, and functions through G proteins to inhibit adenylyl cyclase activity, stimulate phospholipase A2, activate K+ channels, inactivate voltage-dependent Ca2+ channels, and modulate inositol phospholipid hydrolysis. Re
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cently, we have suggested that GABAB receptors activate Kir3.1 and Kir3.2 heterologously expressed in Xenopus oocytes with poly(A)+ RNA derived from rat cerebellum.
We have identified two novel splice variants of the metabotropic γ-aminobutyric acid receptor (GABABR1), designated GABABR1C and GABABR1d, when screening a rat cerebellum cDNA library. GABABR1c has an amino acid sequence identical to GABABR1b, a member of GABABR1 isoforms, and an additional 93-bp insertion that generates an additional 31-amino-acid sequence in the fifth transmembrane region of GABABR1b. Thus, GABABR1c may have a structural variation in the second extracellular loop and fifth transmembrane region. GABABR1d also has an amino acid sequence identical to GABABR1b and an additional insertion of 566 bp that generates a divergent amino acid sequence in thc carboxylterminal end. Reverse-transcription polymerase chain reaction analysis showed that in various rat tissues GABABR1c mRNA was ubiquitously expressed and GABABR1d mRNA in forebrain, cerebellum, eye, kidney, and urinary bladder. GABABR1 isoforms may function not only in the central nervous system but also in various peripheral tissues. Less
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