GABA, ?-hydroxybutyric acid, and neurological disease

Abstract

gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABA is converted from glutamic acid by the action of glutamic acid decarboxylase (GAD) of which two isoforms exist GAD65 and GAD67. GABA then is broken down, both within the cell and in the synaptic cleft by GABA transaminase to form succinic semialdehyde. In turn, succinic semialdehyde is converted either to succinic acid by succinic semialdehyde dehydrogenase or into gamma-hydroxybutyric acid (GHB) by succinic semialdehyde reductase. Because GABA modulates the majority of inhibition that is ongoing in the brain, perturbations in GABAergic inhibition have the potential to result in seizures. Therefore, the most common disorder in which GABA is targeted as a treatment is epilepsy. However, other disorders such as psychiatric disease, spasticity, and stiff-person syndrome all have been related to disorders of GABAergic function in the brain. This review covers the roles of GABAergic neurotransmission in epilepsy, anxiety disorders, schizophrenia, stiff-person syndrome, and premenstrual dysphoric disorder. In the final section of this review, the GABA metabolite GHB is discussed in terms of its physiological significance and its role in epilepsy, sleep disorders, drug and alcohol addiction, and an inborn error of GABA metabolism, succinic semialdehyde dehydrogenase deficiency.

A neuron–glia interaction involving GABA transaminase contributes to sleep loss in sleepless mutants

“…Lastly, disruption of GABAT completely and specifically represses the sleep phenotype of sss p1 , confirming both that GABAT has a role in sleep regulation and that GABAT acts downstream of SSS to modulate sleep. Another sleep promoting molecule downstream of GABAT activity is γ-hydroxybutyric acid (GHB) (36). Due to low similarity of the primary sequence of this enzyme among different species, we are uncertain if Drosophila contains succinic semialdehyde reductase, which catalyzes a product of GABAT, SSA, into GHB.…”

Naked mole rats exhibit metabolic but not ventilatory plasticity following chronic sustained hypoxia

“…The occurrence of VAH has not been explored in naked mole rats but the ventilatory decrease observed during acute hypoxic exposure is partially mediated by an upregulation of inhibitory signalling, with early evidence implicating adenosine as a key regulator of this response [5]. Importantly, a role for g-amino butyric acid (GABA), which is the primary inhibitory neurotransmitter in the adult mammalian central nervous system (CNS), and acts at 25-40% of the synapses within the CNS [10], has yet to be investigated. Relative to glutamate, GABA does not play a major role in the acute HVR or VAH in other small rodents [11,12], however, given the polarity between the HVR of naked mole rats and that of other small rodents (decreased versus increased breathing in acute hypoxia), we hypothesized that GABAergic signalling may be important in regulating the HVR or HMR of naked mole rats to both acute and prolonged hypoxia.…”

Physiological Active Substance Changes of Soybean Curd Residue Fermented by <i>Preussia aemulans</i> and its Bioactivity

“…For γ-Aminobutyric acid, a non-protein amino acid that is widely distributed in nature from microorganisms to plants and animals and it acts as the major inhibitory neurotransmitter in the mammalian central nervous system. In addition, γ-Aminobutyric acid also has hypotensive, tranquilizing and diuretic effects and can prevent diabetes (Wong et al, 2003). For Nucleosides, guanosine has many trophic effects in the central nervous system, including the stimulation of neurotrophic factor synthesis and release by astrocytes, which protect neurons against excitotoxic death (DiIorio et al, 2004).…”