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The Journal of Neuroscience, May 15, 1999, 19(10):3773-3780

Distinct Domains of the CB1 Cannabinoid Receptor Mediate Desensitization and Internalization

Wenzhen Jin¹, Sean Brown², John P. Roche^{2, 3}, Candace Hsieh², Jeremy P. Celver¹, Abraham Kovoor¹, Charles Chavkin¹, and Ken Mackie^{2, 3}

Departments of ¹ Pharmacology, ² Anesthesiology, and ³ Physiology and Biophysics, University of Washington, Seattle, Washington 98195-6540

Desensitization of cannabinoid receptor signaling by a G-protein coupled receptor kinase (GRK) was examined using the Xenopus oocyte expression system. Application of a CB1 agonist, WIN 55,212-2, evoked a concentration-dependent increase in K⁺ conductance (K_ir3) in oocytes coexpressing rat CB1 with the G-protein-gated, inwardly rectifying K⁺ channels K_ir3.1 and K_ir3.4. Desensitization was slight during continuous agonist application in the absence of GRK and arrestin. However, coexpression of GRK3 and -arrestin 2 (-arr2) caused profound homologous CB1 receptor desensitization, supporting the hypothesis that GRK3 and -arr2 effectively produce CB1 receptor desensitization. To identify the regions of the CB1 receptor responsible for GRK3- and -arr2-mediated desensitization, we constructed several CB1 receptor mutants. Truncation of the C-terminal tail of CB1 receptor at residue 418 (418) almost completely abolished desensitization but did not affect agonist activation of K_ir3. In contrast, truncation at residues 439 and 460 did not significantly affect GRK3- and -arr2-dependent desensitization. A deletion mutant (418-439) did not desensitize, indicating that residues within this region are important for GRK3- and -arr2-mediated desensitization. Phosphorylation in this region was likely involved in desensitization, because mutation of either of two putative phosphorylation sites (S426A or S430A) significantly attenuated desensitization. CB1 receptors rapidly internalize after activation by agonist. Phosphorylation of S426 or S430 was not necessary for internalization, because the S426A/S430A CB1 mutant internalized when stably expressed in AtT20 cells. These studies establish that CB1 desensitization can be regulated by a GRK and that different receptor domains are involved in GRK- and -arrestin-dependent desensitization and CB1 internalization.

Key words: cannabinoid; desensitization; inwardly rectifying potassium channel; G-protein-coupled receptor; -arrestin; G-protein coupled receptor kinase; phosphorylation

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19103773-08$05.00/0

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