Pharmacological characterization of the homomeric and heteromeric UNC-49 GABA receptors in C-elegans

被引:45
作者
Bamber, BA
Twyman, RE
Jorgensen, EM
机构
[1] Univ Utah, Dept Pharmacol & Toxicol, Salt Lake City, UT 84112 USA
[2] Univ Utah, Dept Neurol, Salt Lake City, UT 84112 USA
[3] Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA
关键词
UNC-49; GABA(A) receptors; C; elegans; nematodes;
D O I
10.1038/sj.bjp.0705119
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 UNC-49B and UNC-49C are T-aminobutyric acid (GABA) receptor subunits encoded by the Caenorhabditis elegans unc-49 gene. UNC-49B forms a homomeric GABA receptor, or can co-assemble with UNC-49C to form a heteromeric receptor. The pharmacological properties of UNC-49B homomers and UNC-49B/C heteromers were investigated in Xenopus oocytes. 2 The UNC-49 subunits are most closely related to the bicuculline- and benzodiazepine-in sensitive RDL GABA receptors of insects. Consistent with this classification, bicuculline (10 mum) did not inhibit, nor did diazepam (10 mum) enhance UNC-49B homomeric or UNC-49B/C heteromeric receptors. 3 The UNC-49C subunit strongly affects the pharmacology of UNC-49B/C heteromeric receptors. UNC-49B homomers were much more picrotoxin sensitive than UNC-49B/C heteromers (IC50=0.9+/-0.2 mum and 166+/-42 mum, respectively). Pentobarbitone enhancement was greater for UNC-49B homomers compared to UNC-49B/C heteromers. Propofol (50,um) slightly enhanced UNC-49B homomers but slightly inhibited UNC-49B/C heteromers. Penicillin G (10 mm) inhibited UNC-49B homomers less strongly than UNC-49B/C heteromers (30% compared to 53% inhibition, respectively). 4 Several aspects of UNC-49 pharmacology were unusual. Picrotoxin sensitivity strongly correlates with dieldrin sensitivity, yet UNC-49B homomers were highly dieldrin resistant. The enhancing neurosteroid pregnanolone (5beta-pregnan-3alpha-ol-20-one; 10 mum) strongly inhibited both UNC-49 receptors. Alphaxalone (10 mum), another enhancing neurosteroid, did not affect UNC-49B homomers, but slightly inhibited UNC-49B/C heteromers. 5 UNC-49 subunits and mammalian GABA(A) receptor alpha, beta, and gamma subunit classes all share roughly the same degree of sequence similarity. Thus, although they are most similar to other invertebrate GABA receptors, the UNC-49 receptors share significant structural and pharmacological overlap with mammalian GABA(A) receptors. British Journal of Pharmacology (2003).
引用
收藏
页码:883 / 893
页数:11
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