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

Abstract

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.

A Gut Feeling about GABA: Focus on GABAB Receptors

“…It appears at least in some brain regions that GABA B1a and GABA B1b can participate, through heterodimerization with GABA B2 , in the formation of both pre- and post-synaptic receptors. Similar heterodimerization has also been postulated to occur in the GI tract between GABA B1 and GABA B2 (Kawakami et al, 2004) and is further supported by recent immunohistochemical data obtained for both subunits in the upper GI tract (Torashima et al, 2009). …”

“…GABA B2 on the other hand, irrespective of the splice variant examined, was undetectable in either region of the human GI tract (Calver et al, 2000). Despite the initial findings of Calver et al (2000) subsequent studies have identified GABA B2 message in the human lower esophageal sphincter (LES), cardia and corpus (Torashima et al, 2009) as well as in dog intestine (Kawakami et al, 2004). Furthermore, immunohistochemical analysis identified GABA B2 protein on myenteric neurons in human LES and gastric corpus (Torashima et al, 2009).…”

Localization of mGluR5, GABAB, GABAA, and cannabinoid receptors on the vago‐vagal reflex pathway responsible for transient lower esophageal sphincter relaxation in humans: an immunohistochemical study

“…In addition, we demonstrate the presence of GABA B receptors in the myenteric plexus, comparable to a recent study by Torashima et al. 28 These authors demonstrated that both GABA B receptor subtypes are present in the myenteric plexus and form heterodimers. This suggests that the myenteric plexus is a possible site of action of GABA B agonists, thereby contributing to the reduction in TLESRs 11 …”

G-Protein–Coupled Receptors Are Dynamic Regulators of Digestion and Targets for Digestive Diseases

“…Although this heteromerization was first described in the brain, 85 it has been postulated to occur in the digestive tract 87 and is supported by the colocalization of the 2 subunits in the upper gut. 88 GABA A and GABA B receptors are expressed throughout the gut and can regulate relaxation of the lower esophageal sphincter, gastric and intestinal motility, and colonic pain. 89 GABA B agonists have been proposed as a treatment for GERD but the incidence of centrally mediated side effects has limited therapeutic applicability.…”