GABAAα4 Receptor Subunits and Ethanol: A Knockout Punch? Alcoholism: Clinical and Experimental Research (OnlineEarly Articles) 7 Dec 2007
DEFINING THE MOLECULAR sites of action that account for the neurobehavioral effects of ethanol has been an especially difficult task. Both membrane lipids and the proteins that reside there have been examined as targets for the modest and unassuming ethyl alcohol molecule. Over the last 20 years, a great deal of this attention has focused on the widely expressed GABAA family of chloride-conducting ion channels that mediate much of the inhibitory neurotransmission in the adult brain. This is due in large part to the similarities observed between the behavioral actions of ethanol and compounds such as benzodiazepines and barbiturates that are known modulators of GABAA receptor function.m Following the discovery and cloning of the genes that encode members of the GABAA receptor family, a steady and systematic search for ethanol-sensitive GABAA receptors was initiated. To date, there are numerous reports demonstrating that ethanol potentiates the function of various GABAA subunit combinations including those containing the c subunit, a subunit required for sensitivity to benzodiazepines. Yet, in many of these studies, ethanol concentrations required to produce reliable potentiation are uncomfortably high (>50 mM) and are associated with gross intoxication and even death in nontolerant individuals. In contrast to these findings, a recent spate of reports has suggested that a special class of GABAA receptors may be exquisitely sensitive to concentrations of ethanol that are achieved following 1 drink or less. One such member of this family of receptors is thought to be composed of a4 subunits in combination with b and d subunits. These receptors reside outside the gates of the GABAergic synapse where they are exposed to very low ambient levels of GABA. These so-called ‘‘extra’’ synaptic receptors possess a high sensitivity to GABA and a low rate of desensitization allowing them to contribute to the background or tonic level of chloride conductance found in many neurons. This buzz of inhibitory ion flow can be likened to the residual cosmic radiation leftover from the Big Bang and has an important role in regulating neuronal excitability in many brain areas. Interestingly, tonic GABA-mediated currents are enhanced by the action of specific endogenous neurosteroids as well as exogenous pharmacological agents such as Gaboxadol (7-tetra hydroisoxazolo[ 5, 4-c]pyridin-3-ol; THIP) that has been under consideration for use as a sleep aid.
In this issue of ACER, 2 papers appear that examine the effects of ethanol in animals that lack the a4 gene.
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Despite the unexpected findings of Liang et al. (2008) and Chandra et al. (2008), the results of these studies underscore the incredible advances and opportunities that are now available in the alcohol research field. They also stress the importance of combining multiple experimental approaches to better link changes in neurotransmitter signaling pathways to complex ethanol-related behaviors. Finally, they demonstrate the critical need for continued funding of innovative and sophisticated research focused on clearly defining elements that mediate ethanol’s effects on brain and behavior.
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