TABLE 2
Signaling phenotypes of mutant 5-HT1A receptors
Mutant 5-HT1A receptors were grouped according to their responses in the Gαi-mediated (percentage of inhibition of dopamine-stimulated cAMP accumulation) and Gβγ-mediated (DPAT-induced increase in intracellular calcium and Gβγ-mediated stimulation of adenylyl cyclase II) assays. For Gβγ assays, the maximal response produced by wild-type 5-HT1A receptor was designated as 100%. Wild-type-like receptors include mutants with adenylyl cyclase II coupling of ≥50% and calcium mobilization ≥60% of wild-type 5-HT1A receptor, and inhibition of cAMP accumulation ≥30%. Gαi-coupled/weak Gβγ-coupled mutants include receptors that behave like the 5-HT1A-T149A receptor. These mutants had adenylyl cyclase II coupling of ≤30% and calcium mobilization that was 19 to 27% of that of wild-type 5-HT1A receptor and inhibition of cAMP accumulation of 24 to 53%. Uncoupled mutants had undetectable responses. Gβγ-uncoupled mutants include receptors that were uncoupled from both Gβγ responses (calcium mobilization and adenylyl cyclase II) but still retained Gαi function (inhibition of cAMP). Gβγ-selective coupled mutants include receptors that possess at least one intact Gβγ response. Receptors have been separated into two categories: 1) mutants that couple to adenylyl cyclase II stimulation; and 2) mutants that couple to phospholipase Cβ-mediated calcium mobilization. Several receptor mutants also displayed inverse activity. Some mutants inhibited the basal activity of adenylyl cyclase II, and others potentiated DPAT-induced D1 receptor stimulation to increase cAMP accumulation.