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GABAA Receptors As Novel Drug Targets for Treatment of Mental Disorders

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GABAA Receptors As Novel Drug Targets for Treatment of Mental Disorders Journal of Paramedical Sciences (JPS) Summer 2010 Vol.1, No.3 ISSN 2008-496X GABAA receptors as novel drug targets for treatment of mental disorders Abolghasem Esmaeili1,*, Kamran Ghaedi1 1Cell, Molecular & Developmental Biology Division, Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran *Corresponding Author: email address: [email protected] (A. Esmaeili) ABSTRACT A balance between excitatory and inhibitory neurotransmissions in brain is an essential factor for the proper function of the brain. The amino acid gamma-aminobutyric-acid (GABA) is considered as the major inhibitory neurotransmitter in brain. Thus, GABAergic neurons play a key role in regulating behavior. Previous data have revealed the complex subunit structural design for GABAA receptor channel, in which a pentameric assembly resulting from 5 of at least 21 subunits, grouped in the eight classes alpha (α1-6), beta (β1-4), gamma (γ1-4), delta, pi (π), epsilon (ε), theta (θ) and rho (ρ1-3) permits an immense number of putative receptor isoforms. GABAARs are highly diversed in the central nervous system in which this diversity may be related to some mental disorders. Any alteration in expression of the GABAA receptor genes causes neurophysiological and functional consequences that might be associated with neurological disorders. Some neuropsychiatric disorders, such as anxiety, epilepsy and sleep disorders, are effectively treated with therapeutic agents that act on the GABAA receptor. In this article, the contribution of GABAA receptor deficits to central nervous system disorders, in particular anxiety disorders, epilepsy, schizophrenia and insomnia, will be reviewed. The better understanding of GABA and its receptors may help us to find novel therapeutic agents for treatment of mental disorder in future research. Keywords: Epilepsy; Anxiety; Insomnia; Schizophrenia; GABAA receptor subtypes INTRODUCTION functional channels while, gamma subunits are The amino acid gamma-aminobutyric-acid required to mimic the full repertoire of native (GABA) is the major inhibitory receptor for responses to drugs. The neurotransmitter in the CNS [1, 2] that knowledge of the complex pharmacology of mediates most of its effects through receptors GABAA receptors might eventually enable termed GABAA. Previous data have revealed site-directed drug design to elaborate our the complex subunits structural design of this understanding of GABA-related disorders and receptor channel, in which a pentameric of the complex interaction of excitatory and assembly resulting from five of at least 21 inhibitory mechanisms in neuronal processing. subunits, grouped in the eight classes alpha To understand the role of GABAA receptors in (α1-6), beta (β1-4), gamma (γ1-4), delta, pi, mental disorder many methods including epsilon, theta, and rho (ρ1-3) [3-5] permits an molecular and electrophysiological techniques immense number of putative receptor have been used. In the present study we have isoforms. These varieties are extended the shown the role of GABAARs in some mental existence of several splicing variant forms, for disorders. instance of the α6, β2 and γ2 subunits [6]. The subunit combination of GABAA receptor Structure and molecular biology of GABA determines the specific effects of allosteric receptors modulators as benzodiazepines (BZs), The ligand-gated ion channels (LGICs) barbiturates, steroids, and general anaesthetics, super family share a common proposed some convulsants, polyvalent cations, and structure. They have a long extracellular ethanol. These agents act through different amino terminus (around 200 amino acid), binding sites some of which are not identified thought to be responsible for ligand channel yet [7, 8]. Drugs and endogenous ligands bind interactions and forms agonist binding site, either to the extracellular domain or channel and four transmembrane (TM) domains and a domain of the GABAA receptors and act as large intracellular domain between TM3 and positive or negative allosteric modulators [9]. TM4 [2, 10]. The TM3-TM4 loop is an In heterologous expression systems, the important site for regulation by presence of alpha, beta subunits are needed for phosphorylation and for localization at 50 Journal of Paramedical Sciences (JPS) Summer 2010 Vol.1, No.3 ISSN 2008-496X synapses [11]. It is thought that TM2 forms the and 4 genes, which are separated by less than lining segment of the ion channel. The 60-kb, are arranged in the head to head extracellular amino terminus is believed to orientation [17]. The 1 transcription unit faces incorporate neurotransmitter and some the tail of 2. The , and 1 subunit modulator binding sites and it contains a mRNA are predominately expressed in the conserved motif, the so-called Cys loop undifferentiated neuroepithelium of rat embryo (cysteine loop). The Cys-loop is characterized [18]. During postnatal development, down by two cysteine residues spaced by thirteen regulation of the , and 1 subunits otherwise largely divergent amino acid occurs in some specific region whereas residues (Figure.1). This structure is common expression levels of most other subunits within acetylcholine (ACh), glycine and type 3 increase. Highly expression of the , and serotonin (5-HT3) receptor as well. 1 genes in the hippocampal formation of the adult rat [19], shows that cluster organization may be necessary to preserve region-specific gene transcription. The most abundant GABAA receptor subunit genes encoding are found in a 2- cluster on chromosome 5q31.2-q35 [17, 20-24]. The 2 and 6 genes are separated by less than 60-kb, with transcription units facing in opposite directions [17]. The colocalization of the , and 2 subunits may be related to their coordinate gene regulation throughout the nervous system; however, direct observation of Figure 1. Ligand gated ion channels are composed of five peptide units. Each unit has an N-terminal domain, four coordinate regulation has not been reported. transmembrane domains, a large extracellular loop The 6 gene that is head-to-head with 2 is between M3 and M4 and a C-terminus [116]. expressed only in cerebellar granule cells [25], suggests that there is also independent Channels in GABAA and glycine receptors are regulation of transcription for individual anion-selective, whereas in the ACh and 5- members in this gene cluster. HT3 receptors are cation-selective [12]. There The GABAA receptor subunit is a significant sequence homology in each genes are localized on chromosome 15q11– receptor gene family. In GABA receptor A q13 [17, 26-31]. Lastly, the putative subunits the region between TM3 and TM4 gene cluster on chromosome Xq28 is shows a little or no sequence homology, analogous to the cluster on chromosome 15 suggesting that this domain can tolerate many [16, 17, 32, 33]. The -subunit gene is changes without affecting any possible analogous to , and has the same position functional role [13, 14]. GABAA receptors are large proteins (450-627 amino acids in length) and transcriptional orientation as the -subunit embedded in the cell membrane of neurons. gene in other clusters. The channel is formed in the centre of receptor Gene expression can be controlled at that consists of five protein molecules, or multiple levels of transcription, alternative splicing, mRNA stability, translation, post- subunits [15]. GABAA receptors are activated directly by GABA. In this phenomenon they translational modification, intracellular mediate fast response to GABA and open trafficking, and protein degradation. However, channel to allow the inward passage of gene regulation is predominantly controlled at chloride and bicarbonate ions from outside the the level of transcription initiation [34, 35]. cell to inside it. Any abnormal alteration during gene expression could result in changes in function Chromosomal localization of GABAA and could lead to mental disorders. receptor genes It has been found that each GABAA Distribution of GABAA receptor subunits in receptor subunit is encoded by homologous, the CNS distinct genes. Many of the subunit genes are A variety of studies using in situ organized in and gene hybridization [25, 36] and clusters on different chromosomes [16, 17]. In immunohistochemistry [37-41] have indicated humans, the subunit genes are the distribution of GABAA receptor subunits in localized on chromosome 4p14-q12. The 1 the brain. The GABAA receptor α1, β1, β2, β3, 51 Journal of Paramedical Sciences (JPS) Summer 2010 Vol.1, No.3 ISSN 2008-496X and γ2 are found throughout the brain with 23% [43]. These results are in a good different distribution levels. The α2, α3, α4, agreement with in situ hybridization data α5, α6, γ1, and δ subunits are found in certain which showed in the brain that γ1 and γ3 regions of the brain (Table 1). Mehta et al mRNA are expressed in much smaller amounts (1999) reported the percentage of the binding relative to γ2 mRNA [25, 36, 44]. Although sites immunoprecipitated by antisera to these data do not show the regional various subunits of GABAA receptors in the distribution of GABAA receptor subunits, they adult brain regions. These percentages are as show which subunits are abundant in the brain. follows: α1 = 70-90%, α2 = 4-28%, α3 = 12- Distribution of GABAA receptor subunits in 24%, α4 = 0-15%, α5 = 4-14%, α6 = 30-39% the brain are summarised in table 1. Gaba (cerebellum), β1 = 2-32%, β2 = 55-96%, β3 = receptor also could be seen in other tissue far 19-52%, γ1 = 0-19%, γ2 = 50-94%, γ2S = 31- from CNS such as sperm [45]. 52%, γ2L = 37-65%, γ3 = 0-18%, and δ = 0- Table 1. Regional distributions of GABAA receptor subutints in the brain (Sieghart, 2002) 52 Journal of Paramedical Sciences (JPS) Summer 2010 Vol.1, No.3 ISSN 2008-496X Pharmacology of GABAA receptors targets for many important drugs such as More than one hundred agents act on benzodiazepines, general anaesthetics, GABAA receptors. These agents act in steroids, convulsants and barbiturates [51]. different binding sites which some are not Benzodiazepines mediate their sedative, known yet [46]. Drugs and endogenous amnesic and anxiolytic actions via binding ligands act as positive or negative to GABAA receptors.
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