Presence of GABA_B Receptors Forming Heterodimers With GABA_B1 and GABA_B2 Subunits in Human Lower Esophageal Sphincter

Abstract

Baclofen, a GABA_B-receptor (GABA_BR) 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_BR 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_BR 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_BR-forming heterodimers with subunits of GABA_B1 and GABA_B2 are located on the myenteric neurons in human LES, suggesting that GABA_BR agonists and antagonists act at least, at the level of the peripheral nervous system.