Academic journal article Alcohol Research: Current Reviews

Alcohol Dependence and Genes Encoding [Alpha]2 and [Gamma]1 [GABA.Sub.A] Receptor Subunits: Insights from Humans and Mice

Academic journal article Alcohol Research: Current Reviews

Alcohol Dependence and Genes Encoding [Alpha]2 and [Gamma]1 [GABA.Sub.A] Receptor Subunits: Insights from Humans and Mice

Article excerpt

Even though the consequences of alcohol dependence (AD) clearly are devastating and obvious to observers, the molecular mechanisms involved in the development of the disease are far from clear and understood. The search for these mechanisms is made even more difficult by the vast number of genes, proteins, and pathways in the human body that potentially could be involved, and by the obvious limitations of conducting research with human subjects without crossing ethical boundaries. Yet despite these complexities, various approaches already have allowed researchers to gather much knowledge in recent years, and the essential players in alcohol's mechanisms of action and in the development of AD already may have been identified. Thus, research has found that the primary targets of alcohol seem to be proteins prominently involved in neuronal communication, including:

* Ion channels in the neuronal membrane that are activated by signaling molecules (i.e., neurotransmitters) such as [gamma]-aminobutyric acid (GABA) (i.e., [GABA.sub.A] receptors), glycine (i.e., glycine receptors), glutamate (i.e., A-methyl-D-aspartate receptors [NMDA-Rs]), acetylcholine (i.e., nicotinic receptors), and serotonin (i.e., 5-[HT.sub.3] receptors);

* Ion channels regulated by changes in the electric potential across the neuronal membrane (i.e., voltage-gated channels), such as voltage-gated calcium channels; and

* Ion channels regulated by a type of regulatory molecules called G-proteins, such as G-protein--coupled inwardly rectifying potassium channels (GIRKs).

Alcohol's actions on these primary targets trigger the involvement of other systems that ultimately culminate in the development of dependence (Vengeliene et al. 2008).

Many techniques have yielded insight into alcohol's effects on the organism, but perhaps the most challenging field, given the logical ethical constrains, is the study of the neuronal structures and mechanisms that are affected by alcohol and/or which play a role in the development of AD in living humans. One way of circumventing these limitations is by studying how the natural variations (i.e., polymorphisms) between individuals in the genomic DNA relate to AD--that is, whether any specific variants are found more or less commonly than would be expected by chance in people with the disorder. This analysis can provide a glimpse of which genes or gene variants contribute to and shape the development of the disorder.

These natural differences in the genomic DNA between individuals arise from spontaneous mutations of single DNA building blocks (i.e., nucleotides) and are called single nucleotide polymorphisms (SNPs). (For more information on SNPs and their analysis, see the sidebar). In the past 10 years, different genetic association studies in alcohol-dependent subjects have identified several genes linked to this condition. Some examples of proteins that are encoded by genes in which the AD-linked SNPs are located include the following:

* The [mu]-opioid receptor (encoded by the OPRM1 gene) (Bart et al. 2005; Kim et al. 2004; Nishizawa et al. 2006; Ray and Hutchison 2004; Rommelspacher et al. 2001; Zhang et al. 2006);

* The [kappa]-opioid receptor (OPRK1) (Edenberg et al. 2008; Xuei et al. 2006; Zhang et al. 2008);

* Neuropeptide Y (NPY) (Ilveskoski et al. 2001; Lappalainen et al. 2002; Mottagui-Tabar et al. 2005);

* The muscarinic acetylcholine receptor M2 (CHRM2) (Dick et al. 2007; Luo et al. 2005; Wang et al. 2004); and

* The corticotropin-releasing hormone receptor 1 (CRHR1) (Chen et al. 2010).

Another group of genes related to alcohol dependence encode the [GABA.sub.A] receptors ([GABA.sub.A]-Rs). This article will summarize what is known about the role of these receptors in the development of alcohol dependence.

[GABA.sub.A] Receptors

The [GABA.sub.A]-Rs are proteins that span the membrane encasing the nerve cells (i. …

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