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Cross‐Talk Between Membrane‐Initiated and Nuclear‐Initiated Oestrogen Signalling in the Hypothalamus
Author(s) -
Roepke T. A.,
Qiu J.,
Bosch M. A.,
Rønnekleiv O. K.,
Kelly M. J.
Publication year - 2009
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1111/j.1365-2826.2009.01846.x
Subject(s) - agonist , medicine , endocrinology , gq alpha subunit , damgo , receptor , g protein , signal transduction , microbiology and biotechnology , μ opioid receptor , g protein coupled inwardly rectifying potassium channel , chemistry , biology , g protein coupled receptor , functional selectivity , hypothalamus , opioid receptor , biochemistry
It is increasingly evident that 17β‐oestradiol (E 2 ), 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 E 2 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 E 2 ‐BSA and a new ligand (STX) that is selective for the Gq‐mER that does not bind to ERα or ERβ. Both E 2 and STX are fully efficacious in attenuating the GABA B response in ERα, ERβ and GPR 30 knockout mice in an ICI 182 780 reversible manner. These findings are further proof that E 2 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 E 2 , 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, E 2 can activate multiple receptor‐mediated pathways to modulate excitability and gene transcription in CNS neurones that are critical for controlling homeostasis and motivated behaviors.