Received for publication December 7, 2005.
Revised December 8, 2005.
Accepted for publication December 9, 2005.

Novel Features of G Protein-Coupled Receptor Kinase 4 (Relates to Article by Rankin, et al. FastForward 7 December 2005)

Abstract

The defining characteristic of G protein-coupled receptor homologous desensitization is that the receptor must be occupied by an agonist or in an activated conformation that mimics an agonist-induced state. In most instances, the mechanistic basis for this characteristic is the high selectivity of G protein-coupled receptor kinases for the activated receptor. Rankin et al. (p. XXX) now demonstrate that under at least some conditions the G protein-coupled receptor kinase GRK4 does not display a preference for the agonist-occupied D₁ dopamine receptor. Co-expression of GRK4 and the D₁ receptor in a heterologous system induces phosphorylation of the receptor in the absence of agonist, causing constitutive desensitization and internalization of the receptor. Lacking the normal rapid feedback mechanisms associated with homologous desensitization, a system incorporating constitutively active GRK4 will be prone to dysregulation, perhaps explaining the generally low expression of GRK4. Indeed, considerable evidence suggests that just such dysregulation resulting from mutationally activated GRK4 contributes to the heritable component of human essential hypertension (Physiol Genomics 19:223-246, 2004).

Key words: Dopamine, Protein Kinases (other), GRKs, barrestins, Phosphorylation/Dephosphorylation

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