Cross-talk between membrane-initiated and nuclear-initiated oestrogen signalling in the hypothalamus

It is increasingly evident that 17β-oestradiol (E₂), via a distinct membrane oestrogen receptor (Gq-mER), can rapidly activate kinase pathways to have multiple downstream actions in central nervous system (CNS) neurones. We have found that E₂ can rapidly reduce the potency of the GABA_B receptor agonist baclofen and mu-opioid receptor agonist DAMGO to activate G-protein-coupled, inwardly rectifying K⁺ (GIRK) channels in hypothalamic neurones, thereby increasing the excitability (firing activity) of pro-opiomelanocortin (POMC) and dopamine neurones. These effects are mimicked by the membrane impermeant E₂-BSA and a new ligand (STX) that is selective for the Gq-mER that does not bind to ERα or ERβ. Both E₂ and STX are fully efficacious in attenuating the GABA B response in ERα, ERβ and GPR 30 knockout mice in an ICI 182780 reversible manner. These findings are further proof that E₂ signals through a unique plasma membrane ER. We have characterised the coupling of this Gq-mER to a Gq-mediated activation of phospholipase C leading to the up-regulation of protein kinase Cδ and protein kinase A activity in these neurones, which ultimately alters gene transcription. Finally, as proof of principle, we have found that STX, similar to E₂, reduces food intake and body weight gain in ovariectomised females. STX, presumably via the Gq-mER, also regulates gene expression of a number of relevant targets including cation channels and signalling molecules that are critical for regulating (as a prime example) POMC neuronal excitability. Therefore, E₂ can activate multiple receptor-mediated pathways to modulate excitability and gene transcription in CNS neurones that are critical for controlling homeostasis and motivated behaviors.