Contribution of Subunits to Caenorhabditis elegans Levamisole-Sensitive Nicotinic Receptor Function.

HERNANDO G; BERGÉ IGNACIO; D RAYES; BOUZAT C

MOLECULAR PHARMACOLOGY

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Lugar: Baltimore; Año: 2012 vol. 82 p. 550 - 560

0026-895X

C. 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 a-type LEV-8 subunit is a component of native L1 L-AChRs but behaves as a non essential subunit. It plays a key role in maintaining a low rate and extent of desensitization of L-AChRs. In the absence of the a-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 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-p 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. C. 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 a-type LEV-8 subunit is a component of native L1 L-AChRs but behaves as a non essential subunit. It plays a key role in maintaining a low rate and extent of desensitization of L-AChRs. In the absence of the a-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 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-p 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.