The composition of the GABA receptor at the Caenorhabditis elegans neuromuscular junction

被引:43
作者
Bamber, BA
Richmond, JE
Otto, JF
Jorgensen, EM
机构
[1] Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA
[2] Univ Utah, Dept Pharmacol & Toxicol, Salt Lake City, UT 84112 USA
关键词
C; elegans; nematode; neuromuscular junction; GABA(A) receptor; unc-49; subunit composition; synaptic receptor structure; desensitization kinetics;
D O I
10.1038/sj.bjp.0706052
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 The unc-49 gene of the nematode Caenorhabditis elegans encodes three gamma-aminobutyric acid type A (GABA(A)) receptor subunits. Two of these, UNC-49B and UNC-49C, are expressed at high abundance and co-localize at the neuromuscular junction. 2 The UNC-49B subunit is sufficient to form a GABA(A) receptor in vitro and in vivo. Furthermore, all loss-of-function unc-49 alleles lack functional UNC-49B. No mutations specifically inactivate UNC-49C. Thus, UNC-49C appears to be dispensable for receptor function; however, UNC-49C has been conserved among different nematode species, suggesting it plays a necessary role. 3 To ascertain whether UNC-49C is part of the GABA(A) receptor in vivo, we performed patch-clamp electrophysiology on C. elegans muscle cells. Sensitivity to GABA, and to the antagonists picrotoxin and pregnenolone sulfate, matched the UNC-49B/C heteromer rather than the UNC-49B homomer, for both exogenous and synaptically-released GABA. 4 The synaptic localization of UNC-49C requires the presence of UNC-49B, indicative of a physical association between the two subunits in vivo. Thus, the in vivo receptor is an UNC-49B/C heteromer. 5 UNC-49C plays a negative modulatory role. Using the rapid ligand-exchange technique in vitro, we determined that UNC-49C causes accelerated receptor desensitization. Previously, UNC-49C was shown to reduce single-channel conductance in UNC-49B/C heteromers. Thus, the function of UNC-49B is to provide GABA responsiveness and localization to synapses, while the function of UNC-49C is to negatively modulate receptor function and precisely shape inhibitory postsynaptic currents.
引用
收藏
页码:502 / 509
页数:8
相关论文
共 27 条
[21]  
Richmond JE, 1999, NAT NEUROSCI, V2, P791, DOI 10.1038/12160
[22]   The GABA nervous system in C. elegans [J].
Schuske, K ;
Beg, AA ;
Jorgensen, EM .
TRENDS IN NEUROSCIENCES, 2004, 27 (07) :407-414
[23]   The genome sequence of Caenorhabditis briggsae:: A platform for comparative genomics [J].
Stein, LD ;
Bao, ZR ;
Blasiar, D ;
Blumenthal, T ;
Brent, MR ;
Chen, NS ;
Chinwalla, A ;
Clarke, L ;
Clee, C ;
Coghlan, A ;
Coulson, A ;
D'Eustachio, P ;
Fitch, DHA ;
Fulton, LA ;
Fulton, RE ;
Griffiths-Jones, S ;
Harris, TW ;
Hillier, LW ;
Kamath, R ;
Kuwabara, PE ;
Mardis, ER ;
Marra, MA ;
Miner, TL ;
Minx, P ;
Mullikin, JC ;
Plumb, RW ;
Rogers, J ;
Schein, JE ;
Sohrmann, M ;
Spieth, J ;
Stajich, JE ;
Wei, CC ;
Willey, D ;
Wilson, RK ;
Durbin, R ;
Waterston, RH .
PLOS BIOLOGY, 2003, 1 (02) :166-+
[24]   EXPRESSION OF THE HUMAN GLYCINE RECEPTOR ALPHA-1-SUBUNIT IN XENOPUS-OOCYTES - APPARENT AFFINITIES OF AGONISTS INCREASE AT HIGH RECEPTOR DENSITY [J].
TALEB, O ;
BETZ, H .
EMBO JOURNAL, 1994, 13 (06) :1318-1324
[25]   A SINGLE AMINO-ACID IN GAMMA-AMINOBUTYRIC-ACID P1 RECEPTORS AFFECTS COMPETITIVE AND NONCOMPETITIVE COMPONENTS OF PICROTOXIN INHIBITION [J].
WANG, TL ;
HACKAM, AS ;
GUGGINO, WB ;
CUTTING, GR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (25) :11751-11755
[26]  
WHITE G, 1995, RECEPTOR CHANNEL, V3, P1
[27]   GABA, γ-hydroxybutyric acid, and neurological disease [J].
Wong, CGT ;
Bottiglieri, T ;
Snead, OC .
ANNALS OF NEUROLOGY, 2003, 54 :S3-S12