Ethanol-enhanced GABA release: A focus on G protein-coupled receptors

Abstract

While research on the actions of ethanol at the GABAergic synapse has focused on postsynaptic mechanisms, recent data have demonstrated that ethanol also facilitates GABA release from presynaptic terminals in many, but not all, brain regions. The ability of ethanol to increase GABA release can be regulated by different G protein-coupled receptors (GPCRs), such as the cannabinoid-1 receptor, corticotropin-releasing factor 1 receptor, GABA B receptor, and the 5-hydroxytryptamine 2C receptor. The intracellular messengers linked to these GPCRs, including the calcium that is released from internal stores, also play a role in ethanol-enhanced GABA release. Hypotheses are proposed to explain how ethanol interacts with the GPCR pathways to increase GABA release and how this interaction contributes to the brain region specificity of ethanol-enhanced GABA release. Defining the mechanism of ethanol-facilitated GABA release will further our understanding of the GABAergic profile of ethanol and increase our knowledge of how GABAergic neurotransmission may contribute to the intoxicating effects of alcohol and to alcohol dependence.

Activin Controls Ethanol Potentiation of Inhibitory Synaptic Transmission Through GABAA Receptors and Concomitant Behavioral Sedation

“…This seemingly paradoxical finding suggests that the effect of PKCε on ethanol potentiation was reversed in mutant neurons, possibly reflecting (mal) adaptive processes caused by the lack of activin signaling. In addition to allosteric modulation of GABA A Rs, ethanol has also been reported to enhance GABA release (Roberto et al, 2006;Weiner and Valenzuela, 2006;Kelm et al, 2011). We wondered therefore, whether activin would also have an impact on the operation of GABAergic terminals.…”

“…The possible presynaptic loci of ethanol action are still not fully resolved. Likely candidates are presynaptic voltage-dependent Ca 2+ channels and large conductance, Ca 2+ -activated K + channels (BK channels) as well as mechanisms upstream or downstream of G-protein-coupled receptors (Kelm et al, 2011;Li et al, 2014). Gaining insight into the signaling pathways involved in the interplay between activin and ethanol at GABAergic terminals will require substantial future work, given that the presynaptic effects of each substance alone are far from being understood at the mechanistic level.…”

Alcohol and the sleeping brain

“…Alcohol leads to presynaptic release of GABA in the brainstem and spinal cord (Kelm, Criswell, and Breese 2011) and thus, it is reasonable to hypothesize that this sequence plays a role in alcohol’s suppression of REM sleep in the context of high doses of alcohol.…”

Glycine and GABAAUltra-Sensitive Ethanol Receptors as Novel Tools for Alcohol and Brain Research

“…However, these studies involving functional deletion or reduction in receptor sensitivity to ethanol require the use of relatively high ethanol concentrations (10-50 mM) Blednov et al, 2010Blednov et al, , 2011) that may affect other native receptor systems and signaling pathways that modulate additional physiologic processes Harris et al, 2008;Liang et al, 2008;Kumar et al, 2009;Howard et al, 2011;Kelm et al, 2011). In comparison, 17 mM ethanol is equivalent to the 0.08% blood ethanol concentration (BEC) legal driving limit in the United States (Wallner et al, 2003;Ogden and Moskowitz, 2004).…”