A Gut Feeling about GABA: Focus on GABAB Receptors

Abstract

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the body and hence GABA-mediated neurotransmission regulates many physiological functions, including those in the gastrointestinal (GI) tract. GABA is located throughout the GI tract and is found in enteric nerves as well as in endocrine-like cells, implicating GABA as both a neurotransmitter and an endocrine mediator influencing GI function. GABA mediates its effects via GABA receptors which are either ionotropic GABAA or metabotropic GABAB. The latter which respond to the agonist baclofen have been least characterized, however accumulating data suggest that they play a key role in GI function in health and disease. Like GABA, GABAB receptors have been detected throughout the gut of several species in the enteric nervous system, muscle, epithelial layers as well as on endocrine-like cells. Such widespread distribution of this metabotropic GABA receptor is consistent with its significant modulatory role over intestinal motility, gastric emptying, gastric acid secretion, transient lower esophageal sphincter relaxation and visceral sensation of painful colonic stimuli. More intriguing findings, the mechanisms underlying which have yet to be determined, suggest GABAB receptors inhibit GI carcinogenesis and tumor growth. Therefore, the diversity of GI functions regulated by GABAB receptors makes it a potentially useful target in the treatment of several GI disorders. In light of the development of novel compounds such as peripherally acting GABAB receptor agonists, positive allosteric modulators of the GABAB receptor and GABA producing enteric bacteria, we review and summarize current knowledge on the function of GABAB receptors within the GI tract.

Novel functional roles for enteric glia in the gastrointestinal tract

“…Whilst the biological significance of the clearance of neuropeptides is clear, [64][65][66][67] the role of GABA as an enteric transmitter remains to be fully elucidated. 68 Although glial-mediated purine regulation is necessary for normal enteric neurotransmission in situ, 47,58 the necessity of glial-mediated clearance of other classes of neurotransmitters is unknown.…”

Gamma-aminobutyric acid ameliorates gamma rays-induced oxidative stress in the small intestine of rats

“…It has a role in the inhibition of many inflammatory cellular reactions (Tian et al, 2011) and has antidiabetic (Soltani et al, 2011), antioxidant, and free radical-scavenging properties (Deng et al, 2013). GABA is found all over the GI tract, in endocrine-like cells, and in enteric nerves, and it is considered as a neurotransmitter with an endocrine GI tract function (Hyland & Cryan, 2010).…”

Inhibitory system overstimulation plays a role in the pathogenesis of neuromuscular and neurological diseases: a novel hypothesis

“…Administration of benzodiazepines reduces voluntary saccadic eye movement function 42 and increases EEG beta-wave activity 42 , clinical manifestations that also occur in neuromuscular and neurological diseases 18, 43, 44 . Increased GABAergic inhibitory activity can also cause bladder 45, 46 and gastrointestinal dysfunction 47, 48 , both of which can manifest in neuromuscular and neurological diseases 19– 21 . Strikingly, GABAergic activity can also explain the overlapping clinical manifestations between Alzheimer’s disease and alcohol-related dementia 49 , and it can explain the increase in dementia-like symptoms observed after the administration of the benzodiazepine diazepam 50 .…”