Somatostatin receptor desensitization in NG108-15 cells

In NG108-15 cells inhibition of both N-type calcium channel current and ade nylyl cyclase by somatostatin (SRIF) was not sustained but rapidly desensit ized in the continued presence of the drug. The degree and rate of desensit ization were concentration-dependent, and the desensitization was homologou s with respect to the delta-opioid receptor. We have been unable to obtain evidence for the involvement of G protein-coupled receptor kinases (GRKs) i n this desensitization. SRIF-induced desensitization of N-type calcium chan nel currents was not reduced in cells stably overexpressing a dominant nega tive mutant of GRK2 or following intracellular dialysis with GRK2- and GRK3 -blocking peptides or with heparin, Inhibitors of protein kinase A, protein kinase C, and protein kinase G were also without effect. In contrast, both the rate and degree of SRIF-induced desensitization were reduced by pretre atment with phenylarsine oxide or concanavalin A, both inhibitors of recept or endocytosis. Furthermore, SRIF-induced desensitization was enhanced by m onensin, which prevents receptor recycling back to the plasma membrane. Sim ilarly, SRIF-induced desensitization of adenylyl cyclase inhibition was not reduced in cells stably overexpressing dominant negative mutant GRK2 but w as reduced in cells pretreated with the receptor endocytosis inhibitor hype rosmotic sucrose or concanavalin A. These data are consistent with the view that SRIF-induced desensitization in NG108-15 cells results from receptor internalization.