Pregnancy suppresses G protein coupling to phosphoinositide hydrolysis in guinea pig myometrium

The regulatory factors controlling uterine contractile activity during pregnancy remain unclear, although pathways modulating intracellular Ca2+ and prostaglandin production play an important role. Because excitatory hormones raise myometrial Ca2+ levels and prostaglandin output through increasing phosphoinositide hydrolysis, regulation of G protein coupling to phospholipase C activation could be a key site for control. To measure the functional activity of this signaling pathway, we measured formation of [3H]inositol phosphates from prelabeled guinea pig myometrial membranes in response to G protein activation by guanosine 5'-[gamma-thio]triphosphate (GTP gamma S) and fluoride. Although these agents stimulated a three- to fivefold increase in phosphoinositide phospholipase C activity in nonpregnant myometrium, at 46-47, 53-60, and 66-69 days of pregnancy (full term 67 +/- 2 days) this response fell by 43-83%. Moreover, the half-maximal effective dose (ED50) for GTP gamma S action was increased from 8.11 +/- 0.91 nM (n = 5) in the nonpregnant state to 307.4 +/- 142.3 (n = 9) and 209.7 +/- 155.1 nM (n = 8) at 53-60 and 66-69 days, respectively. Because phospholipase C levels displayed only a limited fall (28%) whether measured by direct Ca2+ activation or by immunoblotting, this study indicates a considerable suppression of G protein functional coupling to myometrial phosphoinositide hydrolysis throughout late gestation. Such a desensitization is likely to contribute to reports of diminished contractile sensitivity during pregnancy and to reflect an essential regulatory event in the processes maintaining uterine quiescence in pregnant guinea pig.