Characterization of GABAB Receptor in the Human Colon

Uezono, Yasuhito; Kaibara, Muneshige; Hayashi, Hideki; S, Kawakami; Enjoji, Akihito; Kanematsu, Takashi; Taniyama, Kohtaro

doi:10.1254/jphs.94.211

Cited by 7 publications

(6 citation statements)

References 12 publications

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“…mRNAs for 6 isoforms of GABA B1 subunits: GABA B1(a) , GABA B1(b) , GABA B1(c) , GABA B1(e) , GABA B1(f) , and GABA B1(g) , excluding GABA B1(d) , were detected in the LES and stomach. Similar results have been obtained in colon of dogs (9) and the humans (37). mRNAs for GABA B1(c) , GABA B1(e) , and GABA B1(f) were detected at high levels in the LES and stomach, as compared with the human brain.…”

Section: Discussionsupporting

confidence: 84%

Presence of GABAB Receptors Forming Heterodimers With GABAB1 and GABAB2 Subunits in Human Lower Esophageal Sphincter

et al. 2009

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Abstract. Baclofen, a GABA B -receptor (GABA B R) agonist has been proposed to be useful as therapeutic agent for the management of gastro-esophageal reflux disease, but whether the compound acts directly at the lower esophageal sphincter (LES) remains to be elucidated. We performed the present study to assess the presence of GABA B R in human LES. Western blot analysis showed that both proteins of GABA B1(a) /GABA B1(b) and GABA B2 subunits were present in the muscle layer of LES. Immunohistochemical findings showed that both GABA B1 -and GABA B2 -subunit proteins were located on the neurons within the myenteric plexus, and furthermore, both proteins were observed in the same neurons. Reverse transcriptase-polymerase chain reaction analysis also revealed the presence of mRNAs for both subunits of GABA B R and also mRNAs for 6 isoforms of GABA B1 subunits, from GABA B1(a) to GABA B1(g) , except GABA B1(d) , in human LES. Thus, the functional GABA B R-forming heterodimers with subunits of GABA B1 and GABA B2 are located on the myenteric neurons in human LES, suggesting that GABA B R agonists and antagonists act at least, at the level of the peripheral nervous system.

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Section: Discussionsupporting

confidence: 84%

Presence of GABAB Receptors Forming Heterodimers With GABAB1 and GABAB2 Subunits in Human Lower Esophageal Sphincter

et al. 2009

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“…RT-PCR revealed the expression of both GABA B1 and GABA B2 in the small intestine of dog, as shown previously (30), thereby indicating that the functional GABA B receptors form heterodimers consisted of GABA B1 and GABA B2 , which are possibly located on the enteric cholinergic neurons. Thus, the coupling of GABA B2 with GABA B1 may express a fully functional GABA B receptor, as shown previously (2,3), also in the dog small intestine.…”

Section: Discussionsupporting

confidence: 83%

“…The expected sizes of PCR products using each primer pair are also shown in Table 1. Reverse transcription was carried out as described earlier (30); in a final volume of 20 m l using random primers and a reverse transcriptase supplied with the RT-PCR kit. PCR was done in a final volume of 50 m l containing 1 mM primers, 1 mM of each deoxynucleoside triphosphate (dNTP), 2.5 U of recombinant KOD dash DNA polymerase, and the RT-PCR buffer supplied with the kit.…”

Section: Rt-pcr Of Gaba B -Receptor Mrnasmentioning

confidence: 99%

Characterization of GABAB Receptors Involved in Inhibition of Motility Associated With Acetylcholine Release in the Dog Small Intestine: Possible Existence of a Heterodimer of GABAB1 and GABAB2 Subunits

Uezono

Makimoto

et al. 2004

J Pharmacol Sci

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Abstract. Characterization of the g-aminobutyric acid (GABA) B receptor involved in the motility of dog small intestine was analyzed by application of the microdialysis method to the small intestine of the whole body of the dog. The reverse transcription-polymerase chain reaction (RT-PCR) was used. Intraarterial administration of muscimol induced acceleration of motility associated with acetylcholine (ACh) release, these responses being antagonized by bicuculline. Intraarterial administration of baclofen induced inhibition of motility associated with ACh release, these responses being antagonized by CGP62349. GABA induced inhibition of motility associated with decrease in ACh release. CGP62349 alone induced acceleration of motility associated with increase in ACh release. RT-PCR revealed the presence of mRNAs for both subunits of GABA B receptor, GABA B1 and GABA B2 , in the dog small intestine, although GABA B1 subunits were 6 isoforms of GABA B1 (GABA B1(a) -GABA B1(g) ), except GABA B1(d) . Thus, the GABA B receptor located at cholinergic neurons as a heterodimer with subunits of GABA B1 and GABA B2 in the dog small intestine operates predominantly relative to the GABA A receptor in physiological motility.

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“…Although GABA B R have been localised within the rat and human GI tract, 46 47 crucially we demonstrate for the first time, definitive expression of both GABA B R subunits in human DRG neurons and in colonic DRG neurons from healthy and CVH mice. Taken together these studies demonstrate that activation of GABA B R on human DRG neurons reduces nociceptive signalling, while activation of GABA B R on the peripheral endings of colonic afferents reduces nociception and visceral pain in both healthy and hyperalgesic states.…”

Section: Discussionmentioning

confidence: 63%

α-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABA_Breceptors

Castro

Harrington

Garcia‐Caraballo

et al. 2016

Gut

140

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Objectiveα-Conotoxin Vc1.1 is a small disulfide-bonded peptide from the venom of the marine cone snail Conus victoriae. Vc1.1 has antinociceptive actions in animal models of neuropathic pain, but its applicability to inhibiting human dorsal root ganglion (DRG) neuroexcitability and reducing chronic visceral pain (CVP) is unknown.DesignWe determined the inhibitory actions of Vc1.1 on human DRG neurons and on mouse colonic sensory afferents in healthy and chronic visceral hypersensitivity (CVH) states. In mice, visceral nociception was assessed by neuronal activation within the spinal cord in response to noxious colorectal distension (CRD). Quantitative-reverse-transcription-PCR, single-cell-reverse-transcription-PCR and immunohistochemistry determined γ-aminobutyric acid receptor B (GABABR) and voltage-gated calcium channel (CaV2.2, CaV2.3) expression in human and mouse DRG neurons.ResultsVc1.1 reduced the excitability of human DRG neurons, whereas a synthetic Vc1.1 analogue that is inactive at GABABR did not. Human DRG neurons expressed GABABR and its downstream effector channels CaV2.2 and CaV2.3. Mouse colonic DRG neurons exhibited high GABABR, CaV2.2 and CaV2.3 expression, with upregulation of the CaV2.2 exon-37a variant during CVH. Vc1.1 inhibited mouse colonic afferents ex vivo and nociceptive signalling of noxious CRD into the spinal cord in vivo, with greatest efficacy observed during CVH. A selective GABABR antagonist prevented Vc1.1-induced inhibition, whereas blocking both CaV2.2 and CaV2.3 caused inhibition comparable with Vc1.1 alone.ConclusionsVc1.1-mediated activation of GABABR is a novel mechanism for reducing the excitability of human DRG neurons. Vc1.1-induced activation of GABABR on the peripheral endings of colonic afferents reduces nociceptive signalling. The enhanced antinociceptive actions of Vc1.1 during CVH suggest it is a novel candidate for the treatment for CVP.

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Characterization of GABAB Receptor in the Human Colon

Cited by 7 publications

References 12 publications

Presence of GABAB Receptors Forming Heterodimers With GABAB1 and GABAB2 Subunits in Human Lower Esophageal Sphincter

Presence of GABAB Receptors Forming Heterodimers With GABAB1 and GABAB2 Subunits in Human Lower Esophageal Sphincter

Characterization of GABAB Receptors Involved in Inhibition of Motility Associated With Acetylcholine Release in the Dog Small Intestine: Possible Existence of a Heterodimer of GABAB1 and GABAB2 Subunits

α-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABA_Breceptors

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Characterization of GABAB Receptor in the Human Colon

Cited by 7 publications

References 12 publications

Presence of GABAB Receptors Forming Heterodimers With GABAB1 and GABAB2 Subunits in Human Lower Esophageal Sphincter

Presence of GABAB Receptors Forming Heterodimers With GABAB1 and GABAB2 Subunits in Human Lower Esophageal Sphincter

Characterization of GABAB Receptors Involved in Inhibition of Motility Associated With Acetylcholine Release in the Dog Small Intestine: Possible Existence of a Heterodimer of GABAB1 and GABAB2 Subunits

α-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABABreceptors

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α-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABA_Breceptors