Neuroactive steroids activate membrane progesterone receptors to induce sex specific effects on protein kinase activity

Neuroactive steroids (NAS), which are synthesized in the brain from progesterone, exert potent effects on behavior and are used to treat postpartum depression, yet how these compounds induce sustained modifications in neuronal activity are ill-defined. Here, we examined the efficacy of NAS for membrane progesterone receptors (mPRs) δ and ε, members of a family of GPCRs for progestins that are expressed in the CNS. NAS increase PKC activity via the G_q activation of mPRδ with EC50s between 3 and 11nM. In contrast, they activate G_s via mPRε to potentiate PKA activity with similar potencies. NAS also induced the rapid internalization of only mPRδ. In the forebrain of female mice, mPRδ expression levels were 8-fold higher than in males. Consistent with this, the activation of PKC by NAS was evident in acute brain slices from female mice. Collectively, our results suggest that NAS may exert sex-specific effects on intracellular signaling in the brain via the activation of mPRs.