GABA_A receptor-mediated neurotransmission: Not so simple after all

详细信息    查看全文

• 作者：Fré ; dé ; ric Knoflach^a ; Maria-Clemencia Hernandez^a ; Daniel Bertrand^b ; ^{daniel.bertrand@hiqscreen.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：GABA ; γ-amino-butyric acid ; LGIC ; ligand gated ion channel ; cAMP ; cyclic AMP ; 5HT3 ; 5-hydroxy-triptamine receptor ; PKA ; protein kinase A ; AIS ; axon initial segment ; CCC ; cations chloride cotransporter ; NKCC ; sodium potassium chloride cotransporter ; NCC ; sodium chloride cotransporter ; KCC ; potassium chloride cotransporter ; AD ; Alzheimer&rsquo ; s disease ; ASD ; autism spectrum disorder ; E/I ; excitation/inhibition
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：1 September 2016
• 年：2016
• 卷：115
• 期：Complete
• 页码：10-17
• 全文大小：1128 K

文摘

GABA_A receptors are ligand-gated ion channels that form a fundamental component of inhibitory neurotransmission in the central and peripheral nervous systems. However, since the initial recordings of inhibitory electrical activity of neurons in response to GABA, these receptors have been found to play a more complex role and can, under some circumstances, function in an excitatory manner. This has been demonstrated via electrophysiological recordings conducted in both mature and developing neurons from different brain regions, as well as in various subcellular locations such as dendritic and axonal membranes.

The balance between the inhibitory and excitatory effects mediated by GABA_A receptor activation depends not only on multiple factors that govern the equilibrium of the transmembrane chloride gradient, but also on bicarbonate concentration. Moreover, electrophysiological and fluorescence measurements have revealed that a spatial distribution of the chloride gradient exists within neurons, which locally influences the effects mediated by GABA_A receptor activation. In recent years, it has also become apparent that intra-neuronal chloride concentration is partially regulated by cation-chloride co-transporters (CCCs), in particular NKCC1 and KCC2.

The aim of the present commentary is to discuss, in light of the latest findings, potential implications of the tight spatial and temporal regulation of chloride equilibrium in health and disease, as well as its relevance for the therapeutic effects of molecules acting at GABA_A receptors.