Tibolone rapidly attenuates the GABAB response in hypothalamic neurones
J Qiu1, M A Bosch, O K Rønnekleiv
1Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97239-3098, USA. qiuj@ohsu.edu
Journal of Neuroendocrinology
|December 20, 2008
Summary
Tibolone rapidly impacts brain function by affecting GABA neurotransmission via membrane estrogen receptors, similar to estradiol. This action involves phospholipase C, enhancing synaptic efficacy in key brain circuits.
Area of Science:
- Neuroendocrinology
- Pharmacology
- Cellular Neuroscience
Background:
- Tibolone treats menopausal symptoms and is metabolized into compounds with estrogenic, progestogenic, and androgenic effects.
- Estradiol (E2) rapidly modulates GABA neurotransmission in hypothalamic neurons via membrane estrogen receptors (mER).
- E2 reduces the potency of GABA(B) receptor agonists at G-protein-coupled inwardly rectifying K+ (GIRK) channels.
Purpose of the Study:
- To investigate the rapid signaling pathway of tibolone's action on hypothalamic neurons.
- To determine if tibolone acts through membrane estrogen receptors (mER).
- To elucidate the specific signaling molecules involved in tibolone's effects.
Main Methods:
- Whole-cell patch clamp recordings in ovariectomized guinea pigs and mice.
- Immunocytochemical staining to identify pro-opiomelanocortin (POMC) neurons.
- Utilized selective inhibitors (ER antagonist, phospholipase C, protein kinase inhibitors) and ER alpha/beta knockout models.
Main Results:
- Tibolone and its metabolite 3 beta-hydroxy tibolone, but not other metabolites, reduced GABA(B) receptor agonist potency at GIRK channels in POMC neurons.
- These effects were blocked by an ER antagonist and a phospholipase C inhibitor (U73122).
- Tibolone's effects were independent of ER alpha and ER beta and were not blocked by protein kinase C or A inhibitors.
Conclusions:
- Tibolone and 3 beta-hydroxy tibolone rapidly modulate GABAergic neurotransmission through mER.
- The mechanism involves activation of phospholipase C and subsequent alteration of GIRK channel function, distinct from classical genomic pathways.
- Tibolone may enhance synaptic efficacy via G(q) signaling pathways of mER in brain circuits regulating homeostatic functions.
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