A gut feeling about GABA: focus on GABA(B) receptors

Alimentary Pharmabiotic Centre and Department of Pharmacology and Therapeutics, University College Cork Cork, Ireland.
Frontiers in Pharmacology (Impact Factor: 3.8). 10/2010; 1:124. DOI: 10.3389/fphar.2010.00124
Source: PubMed


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 GABA(A) or metabotropic GABA(B). 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, GABA(B) 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 GABA(B) receptors inhibit GI carcinogenesis and tumor growth. Therefore, the diversity of GI functions regulated by GABA(B) 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 GABA(B) receptor agonists, positive allosteric modulators of the GABA(B) receptor and GABA producing enteric bacteria, we review and summarize current knowledge on the function of GABA(B) receptors within the GI tract.

  • Source
    • ", 2004 ) , indicating that cross talk may exist between the GABAergic and TLR systems , with relevance to inflammatory signaling events . GABA B receptors are metabotropic G i / G o - coupled receptors ( Padgett and Slesinger , 2010 ) which are distributed throughout the CNS and periphery ( Ong and Kerr , 1990 ; Hyland and Cryan , 2010 ) . GABA B receptors can function to regulate ion channels ( activate K + and inhibit Ca 2+ channels ) and cellular signaling ( adenylate cyclase , MAPK ; Kornau , 2006 ; Jiang et al . "
    [Show abstract] [Hide abstract]
    ABSTRACT: The GABAB receptor agonist, baclofen, is used to treat muscle tightness and cramping caused by spasticity in a number of disorders including multiple sclerosis (MS), but its precise mechanism of action is unknown. Neuroinflammation drives the central pathology in MS and is mediated by both immunoreactive glial cells and invading lymphocytes. Furthermore, a body of data indicates that the Toll-like receptor (TLR) family of innate immune receptors is implicated in MS progression. In the present study we investigated whether modulation of GABAB receptors using baclofen can exert anti-inflammatory effects by targeting TLR3 and(or) TLR4-induced inflammatory signaling in murine glial cells and human peripheral blood mononuclear cells (PBMCs) isolated from healthy control individuals and patients with the relapse-remitting (RR) form of MS. TLR3 and TLR4 stimulation promoted the nuclear sequestration of NF-κB and pro-inflammatory cytokine expression in murine glia, while TLR4, but not TLR3, promoted pro-inflammatory cytokine expression in PBMCs isolated from both healthy donors and RR-MS patients. Importantly, this effect was exacerbated in RR-MS patient immune cells. We present further evidence that baclofen dose-dependently attenuated TLR3- and TLR4-induced inflammatory signaling in primary glial cells. Pre-exposure of PBMCs isolated from healthy donors to baclofen attenuated TLR4-induced TNF-α expression, but did not affect TLR4-induced TNF-α expression in RR-MS patient PBMCs. Interestingly, mRNA expression of the GABAB receptor was reduced in PBMCs from RR-MS donors when compared to healthy controls, an effect that might contribute to the differential sensitivity to baclofen seen in healthy and RR-MS patient cells. Overall these findings indicate that baclofen differentially regulates TLR3 and TLR4 signaling in glia and immune cells, and offers insight on the role of baclofen in the treatment of neuroinflammatory disease states including MS.
    Full-text · Article · Aug 2015 · Frontiers in Cellular Neuroscience
  • Source
    • "Recently, it has been demonstrated that the GABA BR1 subunit exists in two isoforms GABA BR1a and GABA BR1b (Pinard et al., 2010). The human GABA B1 gene encodes a third isoform, GABA BR1c , a functional role for which is yet to be determined (Hyland and Cryan, 2010 ). The pre-synaptic GABA B receptors are composed of the GABA BR1a and GABA B2 subunits, whereas the post-synaptic proteins are composed of GABA BR1b and GABA BR2 subunits (Koulen et al., 1998). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Glutamate and γ-aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitter systems, respectively in the central nervous system (CNS). Dysregulation, in any of these or both, has been implicated in various CNS disorders. GABA acts via ionotropic (GABAA and GABAC receptor) and metabotropic (GABAB) receptor. Dysregulation of GABAergic signaling and alteration in GABAB receptor expression has been implicated in various CNS disorders. Clinically, baclofen-a GABAB receptor agonist, is available for the treatment of spasticity, dystonia etc. associated with various neurological disorders. Moreover, GABAB receptor ligands has also been suggested to be beneficial in various neuropsychiatric and neurodegenerative disorders. The present review is aimed to discuss the role of GABAB receptors and the possible outcomes of GABAB receptor modulation in CNS disorders.
    Full-text · Article · Jul 2013 · Pharmacology Biochemistry and Behavior
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Enteric glia are a unique class of peripheral glial cells within the gastrointestinal tract. Major populations of enteric glia are found in enteric ganglia in the myenteric and submucosal plexuses of the enteric nervous system (ENS); these cells are also found outside of the ENS, within the circular muscle and in the lamina propria of the mucosa. These different populations of cells probably represent unique classes of glial cells with differing functions. In the past few years, enteric glia have been found to be involved in almost every gut function including motility, mucosal secretion and host defence. Subepithelial glia seem to have a trophic and supporting relationship with intestinal epithelial cells, but the necessity of these roles in the maintenance of normal epithelial functions remains to be shown. Likewise, glia within enteric ganglia are activated by synaptic stimulation, suggesting an active role in synaptic transmission, but the precise role of glial activation in normal enteric network activity is unclear. Excitingly, enteric glia can also give rise to new neurons, but seemingly only under limited circumstances. In this Review, we discuss the current body of evidence supporting functional roles of enteric glia and identify key gaps in our understanding of the physiology of these unique cells.
    Full-text · Article · Aug 2012 · Nature Reviews Gastroenterology &#38 Hepatology
Show more