Conservation within the RIC-3 gene family. Effectors of mammalian nicotinic acetylcholine receptor expression.
In Caenorhabditis elegans, the ric-3 gene is required for the maturation of multiple nicotinic acetylcholine receptors (nAChRs), whereas other neurotransmittergated channels expressed within the same cells are unaffected by the presence of RIC-3. Here we show that RIC-3 is a member of a conserved gene family with representatives in both vertebrates and invertebrates. All members of this family have two transmembrane domains followed by a coiled-coil domain. Expression of the human ric-3 homolog, hric3, like the C. elegans ric-3, enhances C. elegans DEG-3/DES-2, rat alpha 7, and human alpha 7 nAChR-dependent whole-cell current amplitudes in Xenopus leavis oocytes, thus demonstrating functional conservation. However, hric3 also reduces human alpha 4 beta 2 and alpha 3 beta 4 nAChR-dependent whole-cell current amplitudes. Thus, hric3 shows differential effects on human nAChRs unlike the observed uniform effect of ric-3 on C. elegans nAChRs. Moreover, hric3 totally abolished currents evoked by 5-HT3 serotonin receptors, whereas it barely modified alpha1 glycine receptor currents. With this caveat, RIC-3 belongs to a conserved family of genes likely to regulate nAChR-mediated transmission throughout evolution. Analysis of transcripts encoded by the hric3 locus shows that it encodes for multiple transcripts, likely to produce multiple hric3 isoforms, and that hric3 is expressed in neurons and muscles, thus enabling its interactions with nAChRs in vivo.
Halevi
Sarah
S
Department of Physiology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Yassin
Lina
L
Eshel
Margalit
M
Sala
Francisco
F
Sala
Salvador
S
Criado
Manuel
M
Treinin
Millet
M
D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D017124:Conserved Sequence; D019992:Databases as Topic; D004594:Electrophysiology; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008969:Molecular Sequence Data; D009132:Muscles / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000737:chemistry; D044406:Receptors, Serotonin, 5-HT3; D017422:Sequence Analysis, DNA; D014018:Tissue Distribution; D014981:Xenopus; D014982:Xenopus laevis
D029742:Caenorhabditis elegans Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; C454141:ric-3 protein, C elegans