INVITRO EFFECTS OF 17-BETA-ESTRADIOL ON THE SENSITIVITY OF RECEPTORS COUPLED TO ADENYLATE-CYCLASE ON STRIATAL NEURONS IN PRIMARY CULTURE

Pretreatment of intact striatal neurons from the mouse embryo in primary culture with 17-beta-oestradiol (10(-9) M, 24 hours) enhanced the stimulation of adenylate cyclase activity induced by either dopamine (D1 receptors), isoproterenol, serotonin or 2-chloroadenosine (maximal effective concentrations) but suppressed inhibitory responses evoked by agonists of D2-dopaminergic or enkephalin (mu and delta) receptors. Binding studies indicated that some of these effects are (beta-1) or are not (D1 and D2) associated with changes in the number of receptors. Similar effects were partially seen with testosterone but not with 17-alpha-oestradiol, progesterone or dexamethasone and those induced by 17-beta-oestradiol were abolished when cells were exposed to inhibitors of mRNA transcription (alpha-amanitin) or protein synthesis (cycloheximide). Modifications in the properties of G(s) or G(o,i) proteins were postulated because the number of adenylate cyclase catalytic subunits was not affected by 17-beta-oestradiol pretreatment. Results of ADP-ribosylation experiments with cholera toxin or pertussis toxin and of immunoblot experiments with anti-G-alpha-o and anti-G-beta sera led us to suggest that 17-beta-oestradiol induces qualitative modifications in G(o,i) proteins leading to a stabilization of the associated form of the heterotrimer G-alpha-o,i-beta-gamma. In fact, pretreatment with pertussis toxin (which impairs G-alpha-o,i-beta-gamma-dissociation) mimics the effects of 17-beta-oestradiol on responses of adenylate cyclase to stimulatory and inhibitory agonists.