Contribution of subunits to Caenorhabditis elegans levamisole-sensitive nicotinic receptor function.
Caenorhabditis elegans muscle contains seven different nicotinic receptor (AChR) subunits, five of which have been shown to be components of adult levamisole-sensitive AChRs (L-AChRs). To elucidate the reason for such subunit diversity, we explore their functional roles in larva 1 (L1) muscle cells. Single-channel and macroscopic current recordings reveal that the α-type LEV-8 subunit is a component of native L1 L-AChRs but behaves as a nonessential subunit. It plays a key role in maintaining a low rate and extent of desensitization of L-AChRs. In the absence of the α-type ACR-8 subunit, L-AChR channel properties are not modified, thus indicating that ACR-8 is not a component of L1 L-AChRs. Together with our previous findings, this study reveals that L1 muscle cells express a main L-AChR type composed of five different subunits: UNC-38, UNC-63, UNC-29, LEV-1, and LEV-8. Analysis of a double lev-8; acr-8-null mutant, which shows an uncoordinated and levamisole-resistant phenotype, reveals that ACR-8 can replace LEV-8 in its absence, thus attributing a functional role to this subunit. Docking into homology modeled L-AChRs proposes that ACh forms the typical cation-π interaction, suggests why levamisole is less efficacious than ACh, and shows that ACR-8 can form activatable binding-sites, thus opening doors for elucidating subunit arrangement and anthelmintic selectivity.
Instituto de Investigaciones Bioquímicas de Bahia Blanca, Universidad Nacional del Sur/Consejo Nacional de Investigaciones Científicas y Técnicas, Bahia Blanca, Argentina.
Guillermina
G
Hernando
Ignacio
I
Bergé
Diego
D
Rayes
Cecilia
C
Bouzat
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D007814:Larva / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D007978:Levamisole / Q000494:pharmacology*; D032342:Muscle Cells / Q000187:drug effects* / Q000378:metabolism*; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*
D018501:Antirheumatic Agents; D029742:Caenorhabditis elegans Proteins; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D007978:Levamisole; D000109:Acetylcholine