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

GUILLERMINA HERNANDO; IGNACIO BERGÉ; DIEGO RAYES; CECILIA BOUZAT

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 alpha-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 alpha-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- pi 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.