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J. Biol. Chem., Vol. 280, Issue 29, 27062-27068, July 22, 2005

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Dual Role of the RIC-3 Protein in Trafficking of Serotonin and Nicotinic Acetylcholine Receptors^*

Mar Castillo, José Mulet, Luis M. Gutiérrez, José A. Ortiz, Francisco Castelán, Susana Gerber, Salvador Sala, Francisco Sala, and Manuel Criado¶

From the Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, Apartado 18, 03550 Sant Joan d'Alacant, Alicante, Spain

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 7 nicotinic receptors in Xenopus laevis oocytes, whereas it totally abolishes expression of 42 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 7 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 7 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 7 subunit are required for these actions. Therefore, hRIC-3 can act as a specific regulator of receptor expression at different levels.

Received for publication, April 6, 2005 , and in revised form, May 31, 2005.

^* This work was supported in part by Grants BMC2002-00972 and SAF2002-00209 from the Ministry of Education of Spain and Grants CTIDIB/2002/138 and GRUPOS03/038 from the Generalitat Valenciana.

A scientist of the "Ramón y Cajal" Program from the Ministerio de Educación y Ciencia of Spain.

Recipient of Predoctoral Fellowship 153783 from the Consejo Nacional de Ciencia y Tecnologia of Mexico.

^¶ To whom correspondence should be addressed. Tel.: 34-965919479; Fax. 34-965919484; E-mail: Manuel.Criado{at}umh.es.

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