Dual role of the RIC-3 protein in trafficking of serotonin and nicotinic acetylcholine receptors.
The ric-3 gene is required for maturation of nicotinic acetylcholine receptors in Caenorhabditis elegans. The human homolog of RIC-3, hRIC-3, enhances expression of alpha7 nicotinic receptors in Xenopus laevis oocytes, whereas it totally abolishes expression of alpha4beta2 nicotinic and 5-HT3 serotonergic receptors. Both the N-terminal region of hRIC-3, which contains two transmembrane segments, and the C-terminal region are needed for these differential effects. hRIC-3 inhibits receptor expression by hindering export of mature receptors to the cell membrane. By using chimeric proteins made of alpha7 and 5-HT3 receptors, we have shown that the presence of an extracellular isoleucine close to the first transmembrane receptor fragment is responsible for the transport arrest induced by hRIC-3. Enhancement of alpha7 receptor expression occurs, at least, at two levels: by increasing the number of mature receptors and facilitating its transport to the membrane. Certain amino acids of a putative amphipathic helix present at the large cytoplasmic region of the alpha7 subunit are required for these actions. Therefore, hRIC-3 can act as a specific regulator of receptor expression at different levels.
Castillo
Mar
M
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, Apartado 18, 03550 Sant Joan d'Alacant, Alicante, Spain.
Mulet
José
J
Gutiérrez
Luis M
LM
Ortiz
José A
JA
Castelán
Francisco
F
Gerber
Susana
S
Sala
Salvador
S
Sala
Francisco
F
Criado
Manuel
M
D002352:Carrier Proteins; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D021381:Protein Transport; D011506:Proteins / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D014162:Transfection; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002352:Carrier Proteins; C579167:Chrna7 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C496701:RIC3 protein, human; D011978:Receptors, Nicotinic; D044406:Receptors, Serotonin, 5-HT3; D011993:Recombinant Fusion Proteins; D064569:alpha7 Nicotinic Acetylcholine Receptor; D012701:Serotonin