GABA and GABA receptors

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GABA is the major inhibitory neurotransmitter in the brain. It is formed and degraded in the GABA shunt (Fig. 9.5). Glutamic acid decarboxylase (GAD) converts glutamate to GABA. Promotion of GABA synthesis has been proposed to contribute to the action of some antiepileptic drugs including valproate [56]. GABA is degraded by GABA transaminase to succinic semialdehyde; a-ketoglutarate accepts the amino group in this reaction to become glutamate (Fig. 9.5). GABA is transported into vesicles by the vesicular transporter, VGAT, which has been cloned [57]. Since this transporter is absent from some GABAergic synapses, then other

Gaba Shunt

Fig. 9.5 GABA shunt, a-ketoglutarate and succinic acid are two intermediaries in the Krebs' cycle within the mitochondria. Outside the mitochondria, glutamate is converted to GABA by glutamic acid decarboxylase (GAD). GABA is converted by GABA-transaminase (a mitochondrial enzyme) into succinic semialdehyde and then by succinic semialdehyde dehydrogenase (SSADH) to succinic acid; a-ketoglutarate is converted in this reaction to glutamate.

Fig. 9.5 GABA shunt, a-ketoglutarate and succinic acid are two intermediaries in the Krebs' cycle within the mitochondria. Outside the mitochondria, glutamate is converted to GABA by glutamic acid decarboxylase (GAD). GABA is converted by GABA-transaminase (a mitochondrial enzyme) into succinic semialdehyde and then by succinic semialdehyde dehydrogenase (SSADH) to succinic acid; a-ketoglutarate is converted in this reaction to glutamate.

vesicular transporters probably also exist [58]. GABA acts at three specific receptor types: GABAa, GABAb and GABAC receptors [59]. GABAC receptors are present almost exclusively within the retina where they are responsible for fast chloride currents [59].

GABAa receptors

GABAa receptors are expressed postsynaptically within the brain (presynaptic GABAa receptors have been described within the spinal cord). GABAa receptors are constructed from five of at least 16 mammalian subunits, grouped in seven classes: a, |3, y, 5, o, e and 7t [60], This permits a vast number of putative receptor isoforms. The subunit composition determines the specific effects of allosteric modulators of GABAa receptors, such as neurosteroids, zinc and benzodiazepines [60]. The subunit composition also determines the kinetics of the receptors and can affect desensitization [61]. Importantly the subunit composition of GABAa receptors expressed in neurones can change during epileptogenesis, and these changes influence the pharmacodynamic response to drugs [62], GABAa receptor activation results in the early rapid component of inhibitory transmission. Since GABAa receptors are permeable to chloride and, less so, bicarbonate, the effects of GABAa receptor activation on neuronal voltage are dependent on the chloride and bicarbonate concentration gradients across the membrane [63], In neurones from adult animals, the extracellular chloride concentration is higher than the intracellular concentration resulting in the equilibrium potential of chloride being more negative than the resting potential. Thus GABAa receptor activation results in an influx of chloride and cellular hyperpolarization. This chloride gradient is maintained by a membrane potassium/chloride co-transporter, KCC2 [64], Absence of this transporter in immature neurones results in a more positive reversal potential for chloride, and thus GABAa receptor activation in these neurones produces neuronal depolarization [64,65], During excessive GABAa receptor activation intracellular chloride accumulation can result in depolarizing GABAa receptor-mediated responses. Repetitive stimulation can also have a further paradoxical effect in which the hyperpolarizing GABAa receptor-mediated potential is followed by a prolonged depolarizing potential. This depolarizing potential is partially mediated through an extracellular accumulation of potassium extruded by activation of KCC2 [66]. Thus under certain circumstances GABAa receptors can mediate excitation rather than inhibition. Drugs that inhibit carbonic anhydrase such as acetazolamide and topiramate will reduce the intracellular bicarbonate and thus can reduce these depolarizing GABA responses [67],

Benzodiazepines are specific modulators of GABAa receptors and act at GABAa receptors that contain a al5 a2, a3 or a5 subunit in combination with a y subunit [60]. Drugs acting at the benzodiazepine site have different affinities for the different a subunit containing GABAa receptors, and this specificity can affect pharmacodynamic response [68], This is due perhaps to the varied distribution of these receptors in the brain. Thus the oCj subunit containing receptors seems to have mainly a sedative effect, and is perhaps responsible for this side-effect of benzodiazepines [68]. This also explains why Zolpidem, a drug that has great affinity for GABAa receptors containing the cq subunit, has marked sedative effects and weak anticonvulsant efficacy [69], More selective lig-ands could thus result in benzodiazepine agonists that have less sedative effect and greater anticonvulsant potential. The benzodiazepine's main effect is to increase the affinity of GABAa receptors for GABA, and to increase the probability of receptor opening [70,71]. There has also been the suggestion that benzodiazepines can increase the conductance of high-affinity GABAa receptors [72].

Barbiturates are less selective than benzodiazepines, and potentiate GABAa receptor-mediated currents. The potentiation is partly mediated by prolonging receptor opening times [70,73]. In addition, at high concentrations, they can directly activate the GABAa receptor [60]. This partly explains their anaesthetic effect at high concentrations. Other anaesthetic agents, such as propofol, have similar effects on GABAa receptors [60]. Topiramate can also potentiate GABAa receptors by an unknown mechanism of action [74],

GABAa receptors have other modulatory sites, and can be modulated by zinc [60]. Neurosteroids can also modulate GABAa receptors [60], and variations in neurosteroid levels may explain why seizures occasionally cluster around the time of menstruation [75]. Ganaxolone, a neurosteroid, was, however, dropped from clinical trials due to lack of efficacy [76].

On occasion GABAa receptor agonists can have paradoxical proepileptic effects perhaps due to: GABA being excitatory in some circumstances (see above), synchronization of neurones through the interneuronal network [77,78] or preferential potentiation of GABAergic inhibition of GABAergic interneurones leading to paradoxical disinhibition. GABAa receptor agonists can also exacerbate absence seizures [79]. Absence seizures are generated within a recurrent loop between the thalamus and neocortex, and their generation is dependent upon oscillatory behaviour mediated by GABAa receptors, GABAb receptors, T-type calcium channels and glutamate receptors [79-81], One hypothesis is that hyperpolarization of the thalamocortical neurones in the thalamus mediated by GABAergic inhibition leads to activation of T-type calcium currents which open on neuronal depolarization, resulting in repetitive spiking. This activates neurones in the neocortex which in turn stimulate the thalamic reticular nucleus leading to GABAergic inhibition of the thalamocortical (relay) neurones (Fig. 9.4), and so the cycle continues [79,81], Within this circuit, clonazepam preferentially inhibits the thalamic reticular neurones, perhaps due to the higher expression of a3 containing GABAa receptors [82]. Non-specific GABAa receptor agonists, GABAb receptor agonists or agonists of specific GABAa receptors can all hyperpolarize thalamocortical neurones and so can have a proabsence effect [79]. This also occurs through the potentiation of GABAergic inhibition with ganaxalone [83],

GABAb receptors

GABAb receptors are expressed both pre- and postsynaptically [84,85], They are G-protein-coupled receptors, and consist of dimers of either GABABla or GABABlb and GABAB2 subunits. Activation of GABAB receptors results in inhibition of adenylyl cyclase, inhibition of voltage-gated calcium channels and activation of G protein-linked inwardly rectifying potassium channels (GIRKs). The postsynaptic effect is a prolonged hyperpolarization leading to the late component of inhibitory neurotransmission. At many synapses postsynaptic GABAb receptors are located far from the re lease site, and are only activated by GABA spill-over during simultaneous release of GABA from multiple synapses [86]. Although the effects of this would be to decrease the excitability of the system, GABAB receptor activation may enhance the oscillatory nature of certain structures [86]. Indeed, activation of postsynaptic GABAb receptors in the thalamus has been proposed to underlie the generation of absence seizures [87]. The presynaptic effect of GABAb receptors is not only to inhibit GABA release at inhibitory synapses as a process of autoregulation, but also to inhibit glutamate release at excitatory synapses [85], and thus the effect on the network is complex and difficult to predict. Results with GABAb receptor agonists have been variable, but they seem to have a proabsence effect [79]; conversely, GABAg receptor antagonists have antiabsence effects but can be proconvulsant in other seizure models [88].

GABA uptake and breakdown

Other means of positively modulating GABAergic activity are to inhibit GABA uptake or inhibit GABA breakdown. GABA is mainly metabolized by GABA transaminase to succinic semialdehyde; glutamate is synthesized in this reaction (see above). Vigabatrin irreversibly inhibits GABA transaminase. This results in an increase in intracellular GABA that can produce an increase in vesicular GABA, and so inhibitory transmission [89]. In addition, vigabatrin results in an increase in extracellular GABA that can be partly explained by decreased GABA uptake [90]. GABA released into the extracellular space is transported into neurones and glial cells via Na+/Cl"-coupled GABA transporters (GAT) that can transport GABA against an osmotic gradient [91]. In human and rat, four GAT proteins have been identified and cloned: GAT-1, GAT-2, GAT-3 and BGT-1 [91]. GAT-1 is predominantly present on presynaptic GABAergic terminals and glia, and is the most prevalent GABA transporter in the rat forebrain. In contrast, GAT-3 is localized exclusively to astrocytes and glia, and GAT-2 has a more diffuse distribution. GABA uptake and GAT expression change during development, and are also regulated by protein kinase C (activated by a variety of G-protein receptors), a direct effect of GABA and tyrosine phosphatase [92-95].

Amongst the most potent of GABA transporter inhibitors is nipecotic acid. Nipecotic acid proved to be a useful tool in vitro, but had poor penetration across the blood-brain barrier [96,97], Nipectoic acid was thus only effective in animal epilepsy models, if it was administered intracerebrally. In order to improve the blood-brain penetration of nipecotic acid and similar compounds, a lipophilic side chain was linked to them via an aliphatic chain [98]. This markedly increased the potency and the specificity of these compounds for the GAT-1 transporter as well as increasing brain penetration [99], These compounds, in contrast to nipecotic acid, are not substrates for the transporter [100], One such compound, tiagabine (R-[-]-l-[4,4-fcis(3-methyl-2-thenyl)-3-butenyl]-3-piperidinecarboxylic acid), was selected because of its good preclinical profile [101], Tiagabine is thus a GAT-1 specific, non-transportable, lipid-soluble GABA uptake inhibitor.

Microdialysis studies have demonstrated an increase in extracellular brain GABA concentrations in various brain regions following systemic or local administration of tiagabine [102-105], There does, however, appear to be significant differences in the effect of tiagabine on extracellular GABA between brain areas, perhaps

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  • delma
    What works on the gaba receptors?
    8 years ago

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