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1
* Department of Molecular Pharmacology and Pathology, Consorzio Mario Negri Sud, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Santa Maria Imbaro, Italy;
I.N.M. Neuromed, Pozzilli, Italy; and
Brain Science Institute, RIKEN, Wako-Shi, Saitama, Japan
1Correspondence: Consorzio Mario Negri Sud, via Nazionale 66030 S. Maria Imbaro, Italy. E-mail: deblasi{at}cmns.mnegri.it
G-protein-coupled receptor kinases (GRKs) are involved in the regulation of many G-protein-coupled receptors. As opposed to the other GRKs, such as rhodopsin kinase (GRK1) or ß-adrenergic receptor kinase (ßARK, GRK2), no receptor substrate for GRK4 has been so far identified. Here we show that GRK4 is expressed in cerebellar Purkinje cells, where it regulates mGlu1 metabotropic glutamate receptors, as indicated by the following: 1) When coexpressed in heterologous cells (HEK293), mGlu1 receptor signaling was desensitized by GRK4 in an agonist-dependent manner (homologous desensitization). 2) In transfected HEK293 and in cultured Purkinje cells, the exposure to glutamate agonists induced internalization of the receptor and redistribution of GRK4. There was a substantial colocalization of the receptor and kinase both under basal condition and after internalization. 3) Kinase activity was necessary for desensitizing mGlu1a receptor and agonist-dependent phosphorylation of this receptor was also documented. 4) Antisense treatment of cultured Purkinje cells, which significantly reduced the levels of GRK4 expression, induced a marked modification of the mGlu1-mediated functional response, consistent with an impaired receptor desensitization. The critical role for GRK4 in regulating mGlu1 receptors implicates a major involvement of this kinase in the physiology of Purkinje cell and in motor learning.—Sallese, M., Salvatore, L., D’Urbano, E., Sala, G., Storto, M., Launey, T., Nicoletti, F., Knöpfel, T., De Blasi, A. The G-protein-coupled receptor kinase GRK4 mediates homologous desensitization of metabotropic glutamate receptor 1.
Key Words: Purkinje cells • mGlu1 receptor • receptor internalization • GRK • antisense knock down
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