Activation of Single Nicotinic Receptor Channels from Caenorhabditis elegans Muscle

DIEGO RAYES; MARINA FLAMINI; GUILLERMINA HERNANDO; CECILIA BOUZAT

MOLECULAR PHARMACOLOGY

The American Society for Pharmacology and Experimental Therapeutics

Lugar: Bethesda, Meriland, USA; Año: 2007 vol. 71 p. 1407 - 1415

0026-895X

Nicotinic acetylcholine receptors (nAChRs) are pentameric neu-rotransmitter-gated ion channels that mediate synaptic trans-mission throughout the nervous system in vertebrates and in-vertebrates. Caenorhabditis elegansis a nonmammalian model for the study of the nervous system and a model of parasitic nematodes. Nematode muscle nAChRs are of considerable interest because they are targets for anthelmintic drugs. Weshow single-channel activity of C. elegans muscle nAChRs forthe first time. Our results reveal that in the L1 larval stage acetylcholine (ACh) activates mainly a levamisole-sensitivenAChR (L-AChR). A single population of 39 pS channels, which are 5-fold more sensitive to levamisole than ACh, is detected. Incontrast to mammalian nAChRs, open durations are longer forlevamisole than for ACh. Studies in mutant strains reveal that UNC-38, UNC-63, and UNC-29 subunits are assembled into a single L-AChR in the L1 stage and that these subunits are irreplaceable, suggesting that they are vital for receptor func-tion throughout development. Recordings from a strain mu-tated in the LEV-1 subunit show a main population of channelswith lower conductance (26 pS), prolonged open durations, andreduced sensitivity to levamisole. Thus, although LEV-1 is pref-erentially incorporated into native L-AChRs, receptors lackingthis subunit can still function. No single-channel activity from levamisole-insensitive nAChRs is detected. Thus, during neu-romuscular transmission in C. elegans,the majority of ACh-activated current flows through L-AChRs. This study contrib-utes to the understanding of the molecular mechanisms underlying functional diversity of the nAChR family and offers an excellent strategy to test novel antiparasitic drugs.