Modulation of 5-HT(1A) receptor-mediated Ca(2+) responses by co-expression with various recombinant G(alpha) proteins in CHO-K1 cells.

The ability of the human 5-HT(1A) receptor to activate different recombinant G(alpha) proteins was investigated in CHO-K1 cells by monitoring 5-HT ligand-mediated Ca(2+) responses upon co-expression with either G(alphaq), G(alpha15) or chimeric G(alphaq/i3) proteins. Each G(alpha) protein yielded a typical 5-HT-dependent Ca(2+) response with different kinetic parameters both for the onset-time of maximal Ca(2+) response (21 to 30 s) and time-dependent attenuation (43 to 73% of residual activity at 1 min upon peak Ca(2+) response). Pertussis toxin-treatment fully abolished the Ca(2+) responses mediated by both the endogenous G(i/o) and the chimeric-PTX-sensitive G(alphaq/i3) proteins. In contrast, Ca(2+) responses driven by recombinant G(alphaq) and G(alpha15) proteins were decreased by PTX, respectively by 52% and 35%, corresponding to the level of endogenous G protein activation. The pharmacology of the 5-HT ligand-mediated Ca(2+) responses was highly affected by both the presence and nature of the co-expressed G(alpha) protein. This influence was more pronounced for the partial agonists L 694247, 8-OH-DPAT, flesinoxan and buspirone in contrast to ipsapirone. The G(alpha) protein rank order for apparent increase of ligands' intrinsic activity was: G(alphaq) <G(alphaq/i3) <G(alpha15) protein. Each of the 5-HT-mediated Ca(2+) responses could be antagonised by WAY 100635, buspirone and methiothepin regardless of the absence or presence of a G(alphaq), G(alphaq/i3) or G(alpha15) protein. In conclusion, these data reinforce that depending on the presence and nature of the G(alpha) protein environment, 5-HT(1A) ligands may display a large spectrum of activities.