May the Truth Be with You: Lubiprostone as EP Receptor Agonist/ClC-2 Internalizing “Inhibitor”

Abstract

Chronic constipation is a common clinical problem. Lubiprostone, a bicyclic fatty acid derived from prostaglandin (PG) E1, has been clinically used for the treatment of chronic constipation in adults. Camilleri et al. [1] first reported that lubiprostone inhibited gastric emptying, but accelerated small and large intestinal transit, which is associated with postprandial fullness. Subsequently, on the basis of clinical trials, investigators have reported a beneficial effect of lubiprostone in subjects with chronic constipation and functional bowel disease [2, 3]. Lubiprostone was marketed as belonging to a new therapeutic class, working by a mechanism described as a ClC-2 chloride channel activator. Cuppoletti et al. [4] first reported that lubiprostone increased Cl secretion by activation of the intestinal epithelial cell ClC-2 channel, localized on the apical membrane of enterocytes. Since epithelial Cl secretion is mainly mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) [5], mutations of which cause the disease cystic fibrosis (CF), enhancement of CFTR-independent Cl secretion has been explored as a rescue treatment for CF. Mice with the CFTR mutation DF508, the most common mutation observed in CF patients [6], and CFTR knockout (KO) exhibit an intestinal phenotype, i.e., intestinal obstruction due to loss of Cl secretion, enhancing their utility as models of CF [7]. Nevertheless, the cellular localization and functional roles of epithelial ClC-2 channel and the mechanism of lubiprostone effects on Cl secretion have been questioned. First described in 1992 [8], ClC-2 channels are expressed in the stomach, intestine, colon, brain, heart, and muscles. ClC-2 was first proposed to provide a pathway for epithelial Cl secretion, in addition to CFTR [9]. This hypothesis, however, is not supported by the observation that combined ClC-2 KO/CFTR mutant mice survived longer than CFTR mutant mice, associated with an attenuated intestinal phenotype [10]. Ussing chamber experiments using colonic epithelia suggest that ClC-2 function is localized to the basolateral membrane, facilitating Cl reabsorption rather than Cl secretion. Ussing chamber studies using ClC-2 KO mice also demonstrate that basolateral epithelial ClC-2 has a major function promoting NaCl and fluid absorption, not secretion, in distal colon [11]. Immunohistochemical studies have localized ClC-2 to the basolateral membranes of distal colonic surface enterocytes [12–15], but not to the apical membranes. Therefore, the proposed property of lubiprostone as a ClC2 activator, on the basis of available data, seems questionable [16]. The mechanism of lubiprostone-induced Cl secretion is also controversial. Lubiprostone was originally proposed to increase the open probability of ClC-2 directly, independently of CFTR function [4]. Lubiprostone, however, activated PG E type (EP) receptors, especially EP4 Y. Akiba J. D. Kaunitz Greater Los Angles Veterans Affairs Healthcare System, Los Angeles, CA, USA