GABAA Receptor The GABAA receptor is a member of the superfamily of ligand-activated ion channels in the cell membrane. GABA type A (GABAA) receptors are most closely related to strychnine-sensitive glycine receptors, more distantly related to acetylcholine nicotonic receptors and serotonin 5-hydroxytryptamine (5-HT) [5-HT] type receptors, and even more distantly related to glutamate ionotropic receptors (AMPA and kainate receptors and NMDA receptors). GABAA receptors are heteropentameric protein complexes, which when activated undergo a series of conformational changes that form an open channel (pore) selectively permeable to anions, specifically chlorine anion (Cl–) and to a lesser degree (HCO–3). Receptor activation normally results in an influx of Cl– which rapidly and transiently hyperpolarizes the membrane, a process generally referred to as the generation of an inhibitory postsynaptic potential. The increase in Cl– flux also decreases the resistance of the membrane, which acts as a shunt to impede the ability of depolarizing excitatory postsynaptic potentials to elicit action potentials (nerve impulses).
[...] Not only does positive modulation of these allosteric sites result in anticonvulsant activity, increases in GABA availability also seem to be of clinical benefit. Reduction of GABA clearance by inhibition of GABA uptake or reduction of GABA degradation by poisoning GABA transaminase are both effective. A GABA uptake inhibitor has been recently approved for treatment of partial seizures, but it may exacerbate generalized absence seizures. An irreversible inhibitor of GABA transaminase also effective in the treatment of partial seizures is in the late stages of development. [...]
[...] The basis for the persistent hyperexcitable state remains controversial, and the actual involvement of excitatory amino acid receptors in this hyperexcitable state remains unclear. However, there is good evidence that glutamatergic receptors, particularly NMDA types, play a role in the development and enhancement of the kindled or seizure-prone state. NMDA receptor antagonists can prevent the kindling phenomenon despite the expression of seizurelike discharges in in vitro models such as hippocampal slices. A variety of NMDA antagonists, including those that act as channel inhibitors or compete with the glutamate recognition or glycine recognition sites, appear to be highly effective in blocking the development of kindling. [...]
[...] Chronic Neurodegenerative Disorders Dysregulation of glutamate and aspartate and overactivation of their receptors may contribute neuronal cell loss in chronic disorders such as acquired immune deficiency syndrome (AIDS) dementia, Parkinson's disease, motor neuron disease (including amyotrophic lateral sclerosis), Huntington's disease, and Alzheimer's disease. Tissue-specific defects in glial transporter genes resulting in impaired glutamate uptake have been identified in several cases of the sporadic form of amyotrophic lateral sclerosis. Lathyrism, which is clinically similar to amyotrophic lateral sclerosis, has been linked to the ingestion of cycad beans, which contain an excitotoxin b-N-methylamino-L- alanine. [...]
[...] With the cloning of GABA receptor genes, it is now recognized that the hints of subtypes of GABAA receptors from previous pharmacological experiments are true. This is especially true for subclasses of benzodiazepine-sensitive receptors. Benzodiazepines with greater anxiolytic than sedative-hypnotic properties are in use clinically, and their efficacy may be related to preferential binding to particular subtypes of GABAA receptors. Spasticity Loss of spinal and supraspinal inhibition may result in spasticity or hyperreflexic states. One particular disorder, stiff person syndrome, is associated with increased reflexivity and muscle spasms and occasionally with seizures, diabetes or both in some patients. [...]
[...] AMPA and kainate receptors may also play a role in modulating pain. In situ hybridization studies have revealed that expression of kainate receptor gene GluR5 is particularly prominent in dorsal root ganglion neurons. Animal studies have indicated that kainate receptor antagonists significantly reduce nociception, and early human trials with some of these agents show them to be promising for analgesia. Substance Abuse Several lines of evidence indicate that one of the acute effects of ethanol is to inhibit glutamate receptor function, particularly NMDA and kainate receptors. [...]
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