Cannabinoid receptor CB1 activates the Na+/H+ exchanger NHE-1 isoform via G(i)-mediated mitogen activated protein kinase signaling transduction pathways

We previously showed that the cannabinoid receptor CBI stably transfected i n Chinese hamster ovary cells was constitutively active and could be inhibi ted by the inverse agonist SR 141716A. In the present study, we demonstrate that the cannabinoid agonist CP-55940 induced cytosol alkalinization of CH O-CBI cells in a dose- and time-dependent manner via activation of the Na+/ H+ exchanger NHE-1 isoform, By, contrast, the inverse agonist SR 141716A in duced acidification of the cell cytosol, suggesting that the Na+/H+ exchang er NHE-1 was constitutively activated by the CBI receptor. CB1-mediated NHE 1 activation was prevented by both pertussis toxin treatment and the specif ic MAP kinase inhibitor PD98059, NHE-1 and p42/p44 MAPK had a similar time course of activation in response to the addition of CP-55940 to CHO-CBI cel ls. These results suggest that CB1 stimulates NHE-1 by G(i/o)-mediated acti vation of p42/p44 MAP kinase and highlight a cellular physiological process targeted by CB1. (C) 1999 Federation of European Biochemical Societies.