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Alcohol Research: Current Reviews Units • Ion channels in the neuronal membrane that are activated Alcohol Dependence by signaling molecules (i.e., neurotransmitters) such as γ-aminobutyric acid (GABA) (i.e., GABAA receptors), glycine (i.e., glycine receptors), glutamate (i.e., N-methyl- and genes encoding D-aspartate receptors [NMDA-Rs]), acetylcholine (i.e., nicotinic receptors), and serotonin (i.e., 5-HT3 receptors); α2 and γ1 gABAA • Ion channels regulated by changes in the electric potential across the neuronal membrane (i.e., voltage-gated channels), receptor Subunits such as voltage-gated calcium channels; and Insights from Humans and Mice • 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 cecilia m. Borghese, Ph.D., and r. Adron harris, Ph.D. involvement of other systems that ultimately culminate in one approach to identifying the causes of alcoholism, the development of dependence (Vengeliene et al. 2008). particularly without crossing ethical boundaries in human Many techniques have yielded insight into alcohol’s effects subjects, is to look at the person’s genome (and particularly at on the organism, but perhaps the most challenging field, the variations that naturally arise in the DNA) to identify those given the logical ethical constrains, is the study of the neuronal variations that seem to be found more commonly in people with structures and mechanisms that are affected by alcohol the disease. Some of these analyses have focused on the genes and/or which play a role in the development of AD in living that encode subunits of the receptor for the brain chemical (i.e., humans. One way of circumventing these limitations is by neurotransmitter) γ-aminobutyric acid (GABA). Different studying how the natural variations (i.e., polymorphisms) epidemiological genetic studies have provided evidence that between individuals in the genomic DNA relate to AD— variations in certain GABA receptor (GABA -R) subunits, that is, whether any specific variants are found more or less A A commonly than would be expected by chance in people with particularly subunits α2 and γ1, are correlated with alcohol dependence. Manipulations of these genes and their expression the disorder. This analysis can provide a glimpse of which in mice and rats also are offering clues as to the role of specific genes or gene variants contribute to and shape the develop- GABA -Rs in the molecular mechanisms underlying alcoholism ment of the disorder. A These natural differences in the genomic DNA between and suggest possibilities for new therapeutic approaches. KEY individuals arise from spontaneous mutations of single DNA WORDS: Alcohol dependence; alcoholism; genetic factors; DNA; genetic theory of alcohol and other drug use (AODU); genetic building blocks (i.e., nucleotides) and are called single vulnerability to AODU; genetic variants; γ-aminobutyric acid nucleotide polymorphisms (SNPs). (For more information on SNPs and their analysis, see the sidebar). In the past 10 (GABA); GABAA receptor (GABAA-R) subunits; GABRA2; GABRG1; single nucleotide polymorphisms (SNPs); ion years, different genetic association studies in alcohol-dependent channels; neurotransmitters; gene association studies; human subjects have identified several genes linked to this condition. studies; animal studies; mice; rats Some examples of proteins that are encoded by genes in which the AD-linked SNPs are located include the following: • The µ-opioid receptor (encoded by the OPRM1 gene) ven though the consequences of alcohol dependence (Bart et al. 2005; Kim et al. 2004; Nishizawa et al. 2006; (AD) clearly are devastating and obvious to observers, Ray and Hutchison 2004; Rommelspacher et al. 2001; ethe molecular mechanisms involved in the development Zhang et al. 2006); of the disease are far from clear and understood. The search for these mechanisms is made even more difficult by the vast • The k-opioid receptor (OPRK1) (Edenberg et al. 2008; number of genes, proteins, and pathways in the human body Xuei et al. 2006; Zhang et al. 2008); that potentially could be involved, and by the obvious limi- tations of conducting research with human subjects without crossing ethical boundaries. Yet despite these complexities, cecilia m. Borghese, Ph.D., is a research associate and various approaches already have allowed researchers to gather r. Adron harris, Ph.D., is M. June and J. Virgil Waggoner much knowledge in recent years, and the essential players in Chair in Molecular Biology and director of the Waggoner alcohol’s mechanisms of action and in the development of Center for Alcohol and Addiction Research, both at the AD already may have been identified. Thus, research has found that the primary targets of alcohol seem to be proteins University of Texas at Austin, Austin, Texas. prominently involved in neuronal communication, including: Alcohol Dependence and genes encoding α2 and γ1 gABAA receptor Subunits 345 • Neuropeptide Y (NPY) (Ilveskoski et al. 2001; Lappalainen summarize what is known about the role of these receptors et al. 2002; Mottagui-Tabar et al. 2005); in the development of alcohol dependence. • The muscarinic acetylcholine receptor M2 (CHRM2) (Dick et al. 2007; Luo et al. 2005; Wang et al. 2004); and gABAA receptors • The corticotropin-releasing hormone receptor 1 (CRHR1) The GABAA-Rs are proteins that span the membrane encas- (Chen et al. 2010). ing the nerve cells (i.e., neurons) and which are composed of five subunits arranged around a central pore. There are several Another group of genes related to alcohol dependence classes of subunits, including alpha (α), beta (β), gamma (γ), δ ε θ ρ encode the GABAA receptors (GABAA-Rs). This article will delta ( ), epsilon ( ), pi (π), theta ( ), and rho ( ) subunits. Single-Nucleotide Polymorphisms and Their Analysis What Are Single-Nucleotide in the introduction of a different population. Sometimes, however, Polymorphisms? amino acid, which is called a missense certain combinations of alleles occur Single-nucleotide polymorphisms mutation, or in a premature stop of more or less frequently in a given (SNPs, pronounced “snips”) are the protein, which is called a nonsense population than would be expected spontaneous mutations of single mutation (see the figure). Even if the from random formation of haplotypes. building blocks (i.e., nucleotides) in SNP occurs in a noncoding region of This nonrandom association of alle- the genomic DNA. They can occur the gene, it still may affect regulatory les at two or more loci is referred to randomly, in any region of the DNA, processes that could result, for as linkage disequilibrium. Identification including within those regions of instance, in altered protein levels. of alleles that are in linkage disequi- the gene that actually encode parts When aligning DNA sequences librium can be useful for determin- of the resulting protein (i.e., coding from different individuals and com- ing genes that are involved in condi- sequences), within “silent” regions paring them at the same positions tions such as alcohol dependence. of a gene that ultimately do not (i.e., loci) in the DNA, the occur- encode parts of the resulting protein rence of a SNP results in different How Can SNPs Be Analyzed? (i.e., non-coding regions), or in the “versions” of DNA called alleles. For regions between genes (i.e., inter- example, in the figure, the two alleles Some genetic studies try to determine genic regions). When a SNP occurs for the SNP rs279868 are “A” and whether a certain allele (or haplotype) within a coding sequence, it may “G”. Alleles frequently are transmit- is present more or less frequently in or may not change the amino acid ted from one generation to the next people who suffer from a medical sequence of the encoded protein. in a larger DNA block, usually from condition (e.g., alcoholism) than Each amino acid is represented by a 5,000 to 100,000 nucleotides long. those without the disease; these are three-nucleotide block of DNA (i.e., These blocks, which can contain called genetic-association studies. a codon). Because there are four dif- numerous SNPs, are known as hap- One type of genetic-association studies ferent nucleotides (represented as A, lotypes. Thus, a haplotype specifies are case–control studies, which include C, G, and T), 64 possible codons markers on one member of a pair both individuals affected by the con- exist; however, these encode only 20 of homologous chromosomes (i.e., dition and disease-free control indi- amino acids. As a result, the genetic either the chromosome inherited viduals from the same population. code is degenerate—that is, several from the mother or the one inherited The frequency of alleles then is deter- codons may encode the same amino from the father). mined in both case and control sub- acid (e.g., both ACT and ACC encode Haplotypes are not always trans- jects. Differences in the frequency threonine). A SNP in which both mitted from one generation to the of an allele between the two groups the original codon and the mutant next, however, because of a process suggest that an association exists codon produce the same protein called recombination that randomly between the involved gene and the sequence is called a synonymous occurs during the formation of germ medical condition, with a certain allele polymorphism or silent mutation. cells. As a result of recombination, conferring an increased or decreased If a different polypeptide sequence new haplotypes should be formed risk for the condition. Identification is produced, it is called a replacement based on the frequencies of the dif- of the precise nature of this associa- polymorphism. This can result either ferent alleles involved in the general tion then requires additional studies. 346 Alcohol research: Current Reviews units. The most commonly found GABAA-Rs consist of two which in turn makes it more difficult for the neuron to a, two b, and one g or d subunit.
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