GPBA: a GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation

Abstract

Bile acids (BAs) are digestive secretions that are necessary for the emulsification and absorption of dietary fats. Given the episodic nature of BA secretion and intestinal re-absorption, the circulating and tissue levels of BAs, like those of the gut hormones, fluctuate in fasting and fed states, and BA levels and forms are markedly affected by disease. BAs exert widespread hormonal-like effects by activating receptors in the nucleus and at the plasma membrane. The nuclear steroid receptors mediate the genomic actions of BAs on BA, glucose and lipid homeostasis. GPBA (TGR5) is a G-protein coupled plasma membrane receptor for BAs that mediates many of the rapid, non-genomic actions of BAs. GPBA has been implicated in the control of glucose homeostasis, inflammation and liver functions. Recent observations have revealed an unexpected role for GPBA in the nervous system. GPBA is expressed by enteric neurons and enterochromaffin cells that control peristalsis, and GPBA mediates the prokinetic actions of BAs in the colon that have been known for millennia. GPBA is also present on primary spinal afferent and spinal neurons that are necessary for sensory transduction. BA-induced activation of GPBA in the sensory nervous system promotes scratching behaviours and analgesia, which may contribute to the pruritus and painless jaundice that are observed in some patients with chronic cholestatic disease, where circulating BA concentrations are markedly increased. Thus, GPBA has emerged as an intriguing target for diverse metabolic, inflammatory, digestive and sensory disorders, where agonists and antagonists may be of value. LINKED ARTICLESThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2014.171.issue-5 Abbreviations ADAM, A disintegrin and metalloproteinase domain-containing protein; ASBT, apical sodium-dependent BA transporter; BA, bile acid; CA, cholic acid; CDCA, chenodeoxycholic acid; CGRP, calcitonin gene-related peptide; D2, type 2 iodothyronine deodinase; DCA, deoxycholic acid; GLP-1, glucagon-like peptide 1; GPBA, bile acid receptor; KATP, ATP-dependent potassium channels; LCA, lithocholic acid; OA, oleanolic acid; TDCA, taurodeoxycholic acid; TLCA, taurolithocholic acid; UDCA, ursodeoxycholic acid IntroductionBile acids (BAs), a major component of bile, are digestive secretions that are necessary for the emulsification and absorption of dietary fats. Remarkably, BAs are also signalling molecules. The levels of BAs fluctuate in the circulation under physiological conditions and during disease states, rather like the circulating levels of gut hormones, and BAs can regulate cells throughout the body by activating specific BA receptors in the nucleus and at the plasma membrane. These receptors mediate the effects of BAs on diverse physiological processes, ranging from the control of glucose homeostasis to peristaltic contractions of the digestive tract, and have been implicated in disorders as diverse as obes...

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