Non-classical effects of estradiol on cAMP responsive element binding protein phosphorylation in gonadotropin-releasing hormone neurons: Mechanisms and role

•Estrogens act through indirect and direct pathways to activate CREB in GnRH neurons.•CREB is essential for estrogen negative feedback on GnRH neurons.•There is sex difference in estrogen action on CREB in GnRH neurons.

Gonadotropin-releasing hormone (GnRH) is produced by a heterogenous neuronal population in the hypothalamus to control pituitary gonadotropin production and reproductive function in all mammalian species. Estradiol is a critical component for the communication between the gonads and the central nervous system. Resolving the mechanisms by which estradiol modulates GnRH neurons is critical for the understanding of how fertility is regulated. Extensive studies during the past decades have provided compelling evidence that estradiol has the potential to alter the intracellular signal transduction mechanisms. The common target of many signaling pathways is the phosphorylation of a key transcription factor, the cAMP response element binding protein (CREB). This review first addresses the aspects of estradiol action on CREB phosphorylation (pCREB) in GnRH neurons. Secondly, this review considers the receptors and signaling network that regulates estradiol’s action on pCREB within GnRH neurons and finally it summarizes the physiological significance of CREB to estrogen feedback.