期刊
PHARMACOLOGY & THERAPEUTICS
卷 116, 期 1, 页码 20-34出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pharmthera.2007.03.007
关键词
GABA(A) receptor; neurosteroid; inhibitory synaptic transmissions tonic current; extrasynaptic receptors
资金
- Biotechnology and Biological Sciences Research Council [BB/C509923/1] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/C509923/1] Funding Source: Medline
Certain naturally occurring pregnane steroids act in a nongenomic manner to potently and selectively enhance the interaction of the inhibitory neurotransmitter GABA with the GABA(A) receptor. Consequently such steroids exhibit anxiolytic, anticonvulsam, analgesic, sedative, hypnotic, and anesthetic properties. In both physiological and pathophysiological scenarios, the pregnane steroids may function as endocrine messengers (e.g., produced in the periphery and cross the blood-brain barrier) to influence behaviour. However, additionally neurosteroids can be synthesised in the brain and spinal cord to act in a paracrine or autocrine manner and thereby locally influence neuronal activity. Given the ubiquitous expression of the GABA(A) receptor throughout the mammalian central nervous system (CNS), physiological, pathophysiological, or drug-induced pertubations of neurosteroid levels may be expected to produce widespread changes in brain excitability. However, the neurosteroid/GABA(A) receptor interaction is brain region and indeed neuron specific. The molecular basis of this specificity will be reviewed here, including (1) the importance of the subunit composition of the GABAA receptor; (2) how protein phosphorylation may dynamically influence the sensitivity of GABAA receptors to neurosteroids; (3) the impact of local steroid metabolism; and (4) the emergence of extrasynaptic GABA(A) receptors as a neurosteroid target. (c) 2007 Published by Elsevier Inc.
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