The physiological roles of secretin and its receptor

Abstract

Secretin is secreted by S cells in the small intestine and affects the function of a number of organ systems. Secretin receptors (SR) are expressed in the basolateral domain of several cell types. In addition to regulating the secretion of a number of epithelia (e.g., in the pancreas and biliary epithelium in the liver), secretin exerts trophic effects in several cell types. In this article, we will provide a comprehensive review on the multiple roles of secretin and SR signaling in the regulation of epithelial functions in various organ systems with particular emphasis in the liver. We will discuss the role of secretin and its receptor in health and biliary disease pathogenesis. Finally, we propose future areas of research for the further evaluation of the secretin/secretin receptor axis in liver pathophysiology.

Keywords: Secretin; Secretin receptors.

Figure 1

Ribbon structures for secretin precursor and secretin hormone. The peptide sequence for full-length secretin is 121 aa, and contains multiple stretches capable of hydrogen bonding (red boxes) to support α-helical arrangement. The secretin hormone is 27 aa, and contains one long sequence that supports α-helical formation. 3D structures were predicted with the help of I-tasser software (27,28).

Figure 2

The diagram illustrates that secretin stimulates the secretion of bicarbonate ions by cholangiocytes into the duct lumen by activating cAMP synthesis that induces phosphorylation of PKA, opening of CFTR and activation of the apically located Cl^-/HCO₃^- exchanger AE2.

Figure 3

Diagram depicting the functional heterogeneity of small and large cholangiocytes, lining small and large bile ducts, respectively. Large but not small cholangiocytes are the anatomical sites of secretin-stimulated, cAMP-dependent bicarbonate secretion. Small cholangiocytes secrete water and electrolytes by activation of Ca²⁺-dependent pathways. The cartoon indicates also the possible presence of intra- and extra-hepatic cell compartments in the biliary epithelium.

Figure 4

Ablation of the SR gene (expressed only in cholangiocytes) in 2-wk BDL mice reduces large biliary hyperplasia typical of cholestatic animals. Orig. magn., ×40.