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Novel 7-like nicotinic acetylcholine receptor subunits in the nematode Caenorhabditis elegans

¹ MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK
² Laboratory of Molecular Biophysics, Department of Biochemistry, The Rex Richards Building, University of Oxford, Oxford OX1 3QU, UK
³ The Babraham Institute, Laboratory of Molecular Signalling, Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, UK

Reprint requests to: David B. Sattelle, MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK; e-mail: david.sattelle{at}anat.ox.ac.uk; fax: 441865-282-651.

We have used reverse-transcription-polymerase chain reaction (RT-PCR) and DNA sequencing techniques to confirm the transcription of seven (six and one non-) novel candidate nicotinic acetylcholine receptor (nAChR) subunit-encoding genes identified in the genome sequence of the nematode Caenorhabditis elegans. Compared to vertebrate nAChR subunits, they most closely resemble the homomer-forming, neuronal 7 subunit. Comparison of the predicted amino acid sequences of the new nAChR subunits with those described previously in C. elegans reveals five subunits (four and one non-) which resemble the DEG-3-like group of subunits. To date, this highly divergent nAChR subunit group is unique to C. elegans. ACR-22 is the first non- member of the DEG-3-like group of subunits to be identified. Two new members of the related ACR-16-like nAChR group of subunits have also been shown to be transcribed, making the ACR-16-like subunit group the largest in C. elegans. Residues in the subunit second transmembrane region (M2) which contribute to the channel lining show variations with implications for channel function. For example, in ACR-22, the highly conserved 0` lysine of M2 is replaced by histidine. Restrained molecular dynamics simulations have been used to generate molecular models of homo-pentameric M2 helix bundles for the novel subunits, enabling identification and display of pore-lining and protein interface residues. The number and diversity of genes encoding C. elegans nAChR subunits with similarities to the homomer-forming vertebrate 7 subunits and the identification of related non- subunits, only found in C. elegans to date, suggest that at least some of these subunits may contribute to heteromers in vivo.

Keywords: Nicotinic acetylcholine receptors; Caenorhabditis elegans; ion channel; molecular modeling; 7 subunit

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