Regulation of cholangiocyte bicarbonate secretion

Abstract

The objective of this review article is to discuss the role of secretin and its receptor in the regulation of the secretory activity of intrahepatic bile duct epithelial cells (i.e., cholangiocytes). After a brief overview of cholangiocyte functions, we provide an historical background for the role of secretin and its receptor in the regulation of ductal secretion. We review the newly developed experimental in vivo and in vitro tools, which lead to understanding of the mechanisms of secretin regulation of cholangiocyte functions. After a description of the intracellular mechanisms by which secretin stimulates ductal secretion, we discuss the heterogeneous responses of different-sized intrahepatic bile ducts to gastrointestinal hormones. Furthermore, we outline the role of a number of cooperative factors (e.g., nerves, alkaline phosphatase, gastrointestinal hormones, neuropeptides, and bile acids) in the regulation of secretin-stimulated ductal secretion. Finally, we discuss other factors that may also play an important role in the regulation of secretin-stimulated ductal secretion.

Cyclic AMP Regulates Bicarbonate Secretion in Cholangiocytes Through Release of ATP Into Bile

“…Luminal pH is an indirect measure of bicarbonate secretion, and other transport processes in cholangiocytes can increase luminal pH as well, but available evidence suggest that bicarbonate secretion is the primary process to increase luminal pH in cholangiocytes stimulated with the agonists used in this study (3)(4)(5). Individual isolated IBDUs were placed in a specially designed, temperaturecontrolled chamber mounted on the stage of a Zeiss LSM 510 Laser Scanning Confocal Microscope equipped with a krypton/argon mixed gas laser (Thornwood, NY).…”

“…Because forskolin-mediated secretion involves CFTR (Figure 1b) (3)(4)(5), and activation of CFTR in other systems may result in ATP release (19)(20)(21), we investigated whether forskolin-mediated secretion involves autocrine signaling via luminal ATP. IBDU lumens were perfused with either apyrase to hydrolyze luminal ATP or suramin to block apical P2Y receptors (22).…”

“…The downstream effect of cAMP is to activate the cystic fibrosis transmembrane conductance regulator (CFTR), the apical chloride channel that is defective in cystic fibrosis. Chloride released into the ductular lumen then is thought to be exchanged for bicarbonate via a chloride-bicarbonate exchanger (3)(4)(5). In some systems bicarbonate may be released directly via CFTR, and limited evidence suggests this may occur in cholangiocytes as well (2).…”

“…The second secretory pathway in cholangiocytes is stimulated by neurotransmitters such as acetylcholine (ACh) and autocrine agents such as ATP, and is mediated by cytosolic Ca 2+ (7). The downstream effect of Ca 2+ is to activate Ca 2+ -dependent chloride channels on the apical plasma membrane, which in turn release chloride that is exchanged for bicarbonate via a chloride-bicarbonate exchanger (3)(4)(5). The relative importance of cAMP-dependent and Ca 2+ -dependent ductular secretion is not understood.…”

Wild-type and splice-variant secretin receptors in lung cancer: overexpression in carcinoid tumors and peritumoral lung tissue

“…Although it is difficult to precisely identify the cell type in the alveolar wall expressing secretin receptors, due to resolution limitations of receptor autoradiography, we can exclude a secretin receptor expression in contaminating tumor cells, carcinoid tumorlets, or neuroendocrine cell hyperplasia by morphology and based on the gross tissue distribution patterns of neuroendocrine cell lesion and secretin receptors. 29 Based on close molecular and functional similarities between pneumocytes and secretin receptor expressing cholangiocytes, [30][31][32] we may propose that putative secretin receptor-expressing alveolar epithelial cells regulate transcellular water transport. Furthermore, evidence of secretin receptor mis-splicing was found in these pathological lung tissues.…”