PARTIAL AGONIST ACTIVITY OF 11-CIS-RETINAL IN RHODOPSIN MUTANTS

Rhodopsin, the photoreceptor molecule of the vertebrate rod cell, is a G protein-coupled receptor. Rhodopsin consists of the opsin apoprotei n and its 11-cis-retinal chromophore, which is covalently bound to a s pecific lysine residue by a stable protonated Schiff base linkage, Rho dopsin activation occurs when light causes photoisomerization of the 1 1-cis chromophore to its all-trans form. The all-trans chromophore is the receptor agonist. The 11-cis-retinylidene chromophore is analogous pharmacologically to a potent inverse agonist of the receptor, We rep ort here that replacement of a highly conserved glycine residue (Gly(1 21)) causes 11-cis-retinal to become a pharmacologic partial agonist, Although the mutant apoproteins do not display constitutive activity, they are active in the dark when bound to an 11-cis-retinylidene chrom ophore, or to a ''locked'' chromophore analogue, Ret-7, The degree of partial agonism is directly related to the size of the amino acid repl acement at position 121, and it can be reversed by a specific second-s ite replacement of Phe(261), Thus, mutation of Gly(121) in rhodopsin c auses 11-cis-retinal to act as a partial agonist rather than an invers e agonist, allowing the mutant pigment to activate transducin in the d ark.