MOLECULAR-CLONING OF AN ORPHAN G-PROTEIN-COUPLED RECEPTOR THAT CONSTITUTIVELY ACTIVATES ADENYLATE-CYCLASE

A human gene encoding an orphan G-protein-coupled receptor named ACCA (adenylate cyclase constitutive activator) was isolated from a genomic library using as a probe a DNA fragment obtained by low-stringency PC R. Human ACCA (hACCA) is a protein of 330 amino acids that exhibits al l the structural hallmarks of the main family of G-protein-coupled rec eptors. Expression of hACCA resulted:in a dramatic stimulation of aden ylate cyclase, similar in amplitude to that obtained with other G(s)-c oupled receptors fully activated by their respective ligands. This sti mulation was obtained in a large variety of stable cell lines derived from various organs, and originating from different mammalian species, hACCA was found to be the human homologue of a recently reported mous e orphan receptor (GPCR21). The mouse ACCA (mACCA) was therefore reclo ned by PCR, and expression of mACCA in Cos-7 cells demonstrated that t he mouse receptor behaved similarly as a constitutive activator of ade nylate cyclase. It is not known presently whether the stimulation of a denylate cyclase is the result of a true constitutive activity of the receptor or, alternatively, is the consequence of a permanent stimulat ion by a ubiquitous ligand. The tissue distribution of mACCA was deter mined by RNase protection assay. Abundant transcripts were found in th e brain, whereas lower amounts were detected in testis, ovary and eye. Various hypotheses concerning the constitutive activity of ACCA and t heir potential biological significance are discussed.