Abstract
RHODOPSIN kinase1 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 membrane3,4. 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) isoprenoid5 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 βARK), which lack an intrinsic lipid, are activated6 on exposure to brain βγ subunits of the signal-transducing G proteins, the γ subunit of which bears a 20-C (geranylgeranyl) isoprenoid7,8. 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.
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Inglese, J., Koch, W., Caron, M. et al. Isoprenylation in regulation of signal transduction by G-protein-coupled receptor kinases. Nature 359, 147–150 (1992). https://doi.org/10.1038/359147a0
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DOI: https://doi.org/10.1038/359147a0
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