Heterotrimeric guanine nucleotide-binding (G) protein-coupled receptor kinases (GRKs) are cytosolic proteins that contribute to the adaptation of G proteincoupled receptor signaling. The canonical model for GRK-dependent receptor desensitization involves GRKmediated receptor phosphorylation to promote the binding of arrestin proteins that sterically block receptor coupling to G proteins. However, GRK-mediated desensitization, in the absence of phosphorylation and arrestin binding, has been reported for metabotropic glutamate receptor 1 (mGluR1) and ␥-aminobutyric acid B receptors. Here we show that GRK2 mutants impaired in G␣ q/11 binding (R106A, D110A, and M114A), bind effectively to mGluR1a, but do not mediate mGluR1a adaptation. G␣ q/11 is immunoprecipitated as a complex with mGluR1a in the absence of agonist, and either agonist treatment or GRK2 overexpression promotes the dissociation of the receptor/G␣ q/11 complex. However, these mGluR1a/G␣ q/11 interactions are not antagonized by the overexpression of either GRK2 mutants defective in G␣ q/11 binding or RGS4. We have also identified a GRK2-D527A mutant that binds G␣ q/11 in an AlF 4 ؊ -dependent manner but is unable to either bind mGluR1a or attenuate mGluR1a signaling. We conclude that the mechanism underlying GRK2 phosphorylation-independent attenuation of mGluR1a signaling is RH domaindependent, requiring the binding of GRK2 to both G␣ q/11 and mGluR1a. This serves to coordinate GRK2 interactions with G␣ q/11 and to disrupt receptor/G␣ q/11 complexes. Our findings indicate that GRK2 regulates receptor/G protein interactions, in addition to its traditional role as a receptor kinase.

, and irx4 in outflow segment precursors of the primary heart field. In addition, the sinoatrial-enriched transcription factor, tbx5, was ectopically expressed in the primitive ventricle and ventricle-specific splicing of mef2b was lost, suggesting that the mutant ventricle had acquired atrial-specific characteristics. Collectively, these results suggest a fundamental role of MEF2C in ventricular cardiomyocyte differentiation and apportioning of cells between inflow and outflow precursors in the primary heart field.