Isoprenylation in regulation of signal transduction by G-protein-coupled receptor kinases

RHODOPSIN kinase 1 and β -adrenergic receptor kinase ( β ARK) 2 are related members of a serine/threonine kinase family that specifically initiate deactivation of G-protein-coupled receptors. After stimulus-mediated receptor activation, these cytoplasmic kinases translocate to the plasma membrane 3,4 . Here we show that the molecular basis for this event involves a class of unsaturated lipids called isoprenoids. Covalent modification in vivo of rhodopsin kinase by a 15-C (farnesyl) isoprenoid 5 enables the kinase to anchor to photon-activated rhodopsin. Mutations that alter or eliminate the isoprenoid, fully disable light-specific Rhodopsin kinase translocation. Other receptor kinases (such as β ARK), which lack an intrinsic lipid, are activated 6 on exposure to brain βγ subunits of the signal-transducing G proteins, the γ subunit of which bears a 20-C (geranylgeranyl) isoprenoid 7,8 . Using chimaeric β ARKs that undergo isoprenylation in vitro , we demonstrate that membrane association and activation of these kinases can occur in the absence of βγ . These results indicate that rhodopsin kinase (by means of an integral isoprenoid) and β ARK (through its association with βγ ) both rely on the function of isoprenyl moieties for their translocation and activity, illustrating distinct, though related, modes of biological regulation of receptor function.