Functions and roles of the extracellular Ca2+-sensing receptor in the gastrointestinal tract
Introduction
Ca2+-sensing receptor transcripts and/or protein are expressed in the gastrointestinal tracts of fish [1], birds [2], amphibia [3], [4] and mammals [5], [6], [7], [8], [9], [10] including human [5], [11], [12]. Expression of the receptor in the gastrointestinal tract goes back in evolution at least as far as cartilaginous fish (elasmobranchs), e.g., the dogfish shark [1]. In both cartilaginous and bony fish, the Ca2+-sensing receptor is present on apical surfaces of stomach and intestine [1]. Recent evidence suggests that the Ca2+-sensing receptor may have evolved in the early marine environment to support osmo-adaptation. This latter notion is supported by the more general expression of the Ca2+-sensing receptor in many other tissues outside the gastrointestinal tract that are involved in mono- and di-valent transport into and out of fish that live in a seawater environment rich in divalent minerals and sodium chloride [1], [13]. This theme of the Ca2+-sensing receptor linking divalent and monovalent metabolism is echoed in mammals (e.g., effects of the receptor on fluid transport by the colon; to be discussed latter in this chapter).
In the amphibian, Necturus maculosus, Ca2+-sensing receptor expression was detected on the basal aspect of gastric epithelial cells [3]. In contrast in the frog stomach, Ca2+-sensing receptor expression was observed on the apical membranes of acid-secreting oxyntic cells [4]. In the chicken, Gallus domesticus, receptor was detected in the duodenum, but other gastrointestinal tissues were not assayed [2]. In mammals, a more complete exploration of Ca2+-sensing receptor expression along the gastrointestinal tract has been performed [5], [6], [7], [8], [9], [10], [12]. Receptor transcripts and/or protein have been detected in the stomach, the small intestinal and colonic mucosal epithelia, and the underlying neural plexuses of Meissner and Auerbach. Ca2+-sensing receptor has also been detected in several human intestinal cell lines (T84, HT-29, Caco-2, FET, SW480, MOSER and CBS; [8], [14], [15], [16]) as well as in primary cultures of human gastric mucosa [11], [17], [18].
In the mammalian stomach, the Ca2+-sensing receptor is located on both apical and basolateral membranes of human G-cells (gastrin secreting cells; [17], [18]) and mucous secreting cells [11] and on basolateral membranes of parietal cells [4], [6], [19]. In small intestine, both apical and basolateral membranes of villus cells express the Ca2+-sensing receptor [7]. In rat colon, receptor is also expressed on both apical and basolateral membranes of surface and crypt epithelial cells [5], [7]. A similar pattern of Ca2+-sensing receptor immunostaining was observed in both the proximal and distal colon of rat [5]. In human large intestine, Ca2+-sensing receptor has also been identified on both apical and basolateral membranes of crypts as well as in certain enteroendocrine cells at the base of crypts [5], [12].
Section snippets
Overview
In order to generate the large quantities of 0.16N hydrochloric acid needed for digestion of ingested food, the mammalian stomach has developed a complex series of neuronal, hormonal and/or paracrine/autocrine feedback regulatory mechanisms [20], [21], [22], [23] which allow for the continued production of acid. A model of acid secretion by the parietal cell is shown in Fig. 1 that summarizes data from many laboratories [21], [22], [24], [25], [26]. Protons combined with the secreted Cl−
Overview
While the Ca2+-sensing receptor is expressed in epithelial cells along the entire small and large intestine, only the receptor in colon has been studied in sufficient detail to permit comment on the potential roles of the receptor in normal intestinal function, in diarrheal states and in the effect of oral Ca2+ intake on the risk of colon cancer. The expression of the Ca2+-sensing receptor in nerve plexi involved in smooth muscle function and coordination, however, suggests a potential role in
Overview
The epithelium of the colon, as well as the small intestine, is in a state of constant renewal. In colon, cells proliferate and become differentiated as they migrate out of the base of the crypt to the surface. Thus, cells at the base of the crypt are highly proliferative but less differentiated, whereas cells at the surface of the colon are highly differentiated and are in a non-proliferative state. Alterations of this highly regulated process may lead to the development of tumors. A potential
Summary
Fig. 6 presents a summary of the potential roles of the Ca2+-sensing receptor in gastrointestinal biology. Because of the unique properties of the Ca2+-sensing receptor in recognizing and responding to extracellular Cao2+ and nutrients, this receptor provides potential mechanisms linking dietary metabolism (i.e., food digestion and nutrient absorption) to link: (1) nutrient availability to epithelial growth and differentiation; (2) protein and divalent mineral metabolism; (3) dietary Ca2+
Acknowledgements
SCH, SXC and JPG are supported by grants from the Broad Foundation. SCH and JPG are supported by grants from the National Institutes of Health (DK50230 and DK60069 to JPG and DK38603 and DK54999 to SCH).
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