Elsevier

Cell Calcium

Volume 35, Issue 3, March 2004, Pages 239-247
Cell Calcium

Functions and roles of the extracellular Ca2+-sensing receptor in the gastrointestinal tract

https://doi.org/10.1016/j.ceca.2003.10.015Get rights and content

Abstract

The gastrointestinal tract is vital to food digestion and nutrient absorption as well as normal salt and water homeostasis. Studies over the last several years have shown that the Ca2+-sensing receptor is expressed along the entire gastrointestinal tract. The potential roles for the receptor in gastrointestinal biology are now only beginning to be elucidated and much work remains. Well-studied physiological effects include regulation of gastric acid secretion and modulation of fluid transport in the colon. It remains to be determined if the Ca2+-sensing receptor is involved in calcium handling by the gastrointestinal tract. The ability of organic nutrient receptor agonists/allosteric modifiers, such as polyamines and l-amino acids, to activate the Ca2+-sensing receptor suggest potential roles in signalling nutrient availability to gastric and intestinal epithelial cells. In addition, polyamines are crucial for normal cell proliferation and differentiation required to sustain the rapid turnover of gastrointestinal epithelial cells and the Ca2+-sensing receptor may be involved in this function. Activation of the colonic Ca2+-sensing receptor can abrogate cyclic nucleotide-mediated fluid secretion suggesting a role for the receptor in modifying secretory diarrheas like cholera. Finally, the Ca2+-sensing receptor has been suggested to provide a mechanism for the effect of calcium intake in reducing the risk of colon cancer.

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).

References (97)

  • J. Geibel et al.

    Gastrin-stimulated changes in Ca2+ concentration in parietal cells depends on adenosine 3′,5′-cyclic monophosphate levels

    Gastroenterology

    (1995)
  • A. Itami et al.

    Human gastrinoma cells express calcium-sensing receptor

    Life Sci.

    (2001)
  • J.B. Jansen et al.

    Effect of changes in serum calcium on secretin-stimulated serum gastrin in patients with Zollinger-Ellison syndrome

    Gastroenterology

    (1982)
  • J.P. Raufman

    Cholera

    Am. J. Med.

    (1998)
  • H.J. Binder et al.

    Novel transport properties of colonic crypt cells: fluid absorption and Cl-dependent Na–H exchange

    Comp. Biochem. Physiol. A Physiol.

    (1997)
  • Y. Oda et al.

    The calcium sensing receptor and its alternatively spliced form in murine epidermal differentiation

    J. Biol. Chem.

    (2000)
  • Y. Oda et al.

    The calcium sensing receptor and its alternatively spliced form in keratinocyte differentiation

    J. Biol. Chem.

    (1998)
  • C.L. Tu et al.

    Effects of a calcium receptor activator on the cellular response to calcium in human keratinocytes

    J. Invest. Dermatol.

    (1999)
  • D.D. Bikle et al.

    Calcium- and vitamin D-regulated keratinocyte differentiation

    Mol. Cell Endocrinol.

    (2001)
  • K.I. Lin et al.

    Elevated extracellular calcium can prevent apoptosis via the calcium-sensing receptor

    Biochem. Biophys. Res. Commun.

    (1998)
  • S.E. McNeil et al.

    Functional calcium-sensing receptors in rat fibroblasts are required for activation of SRC kinase and mitogen-activated protein kinase in response to extracellular calcium

    J. Biol. Chem.

    (1998)
  • C. Dufour et al.

    Spermine and spermidine induce intestinal maturation in the rat

    Gastroenterology

    (1988)
  • N. Seiler et al.

    Polyamine transport in mammalian cells. An update

    Int. J. Biochem. Cell Biol.

    (1996)
  • N.A. Wong et al.

    Beta-catenin—a linchpin in colorectal carcinogenesis?

    Am. J. Pathol.

    (2002)
  • T. Yamaguchi et al.

    Activation of p42/44 and p38 mitogen-activated protein kinases by extracellular calcium-sensing receptor agonists induces mitogenic responses in the mouse osteoblastic MC3T3-E1 cell line

    Biochem. Biophys. Res. Commun.

    (2000)
  • T. Yamaguchi et al.

    The extracellular calcium (Cao2+)-sensing receptor is expressed in myeloma cells and modulates cell proliferation

    Biochem. Biophys. Res. Commun.

    (2002)
  • S.A. Hobson et al.

    Signal transduction mechanisms linking increased extracellular calcium to proliferation in ovarian surface epithelial cells

    Exp. Cell Res.

    (2000)
  • R.S. Bresalier

    Calcium, chemoprevention, and cancer: a small step forward (a long way to go)

    Gastroenterology

    (1999)
  • C. Garland et al.

    Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men

    Lancet

    (1985)
  • B.C. Pence

    Role of calcium in colon cancer prevention: experimental and clinical studies

    Mutat. Res.

    (1993)
  • J.E. Kerstetter et al.

    Dietary protein, calcium metabolism, and skeletal homeostasis revisited

    Am. J. Clin. Nutr.

    (2003)
  • J.E. Kerstetter et al.

    Dietary protein affects intestinal calcium absorption

    Am. J. Clin. Nutr.

    (1998)
  • J.E. Kerstetter et al.

    A threshold for low-protein-diet-induced elevations in parathyroid hormone

    Am. J. Clin. Nutr.

    (2000)
  • R.P. Heaney

    Dietary protein and phosphorus do not affect calcium absorption

    Am. J. Clin. Nutr.

    (2000)
  • J. Nearing et al.

    Polyvalent cation receptor proteins (CaRs) are salinity sensors in fish

    Proc. Natl. Acad. Sci. U.S.A.

    (2002)
  • R. Diaz et al.

    Cloning, expression, and tissue localization of the calcium-sensing receptor in chicken (Gallus domesticus)

    Am. J. Physiol.

    (1997)
  • R.R. Cima et al.

    Identification and functional assay of an extracellular calcium-sensing receptor in Necturus gastric mucosa

    Am. J. Physiol. (Gastrointest. Liver Physiol.)

    (1997)
  • R. Caroppo et al.

    Asymmetrical, agonist-induced fluctuations in local extracellular [Ca2+] in intact polarized epithelia

    EMBO J.

    (2001)
  • S.X. Cheng et al.

    Expression of calcium-sensing receptor in rat colonic epithelium: evidence for modulation of fluid transport

    Am. J. Physiol. (Gastrointest. Liver Physiol.)

    (2002)
  • N. Chattopadhyay et al.

    Identification and localization of extracellular Ca2+-sensing receptor in rat intestine

    Am. J. Physiol. (Gastrointest. Liver Physiol.)

    (1998)
  • L. Gama et al.

    Ca2+-sensing receptors in intestinal epithelium

    Am. J. Physiol.

    (1997)
  • T. Mitsuma et al.

    Distribution of calcium sensing receptor in rats: an immunohistochemical study

    Endocr. Regul.

    (1999)
  • R.R. Butters et al.

    Cloning and characterization of a calcium-sensing receptor from the hypercalcemic New Zealand white rabbit reveals unaltered responsiveness to extracellular calcium

    J. Bone Miner. Res.

    (1997)
  • M.J. Rutten et al.

    Identification of a functional Ca2+-sensing receptor in normal human gastric mucous epithelial cells

    Am. J. Physiol.

    (1999)
  • Y. Sheinin et al.

    Immunocytochemical localization of the extracellular calcium-sensing receptor in normal and malignant human large intestinal mucosa

    J. Histochem. Cytochem.

    (2000)
  • H. Hentschel et al.

    Localization of Mg2+-sensing shark kidney calcium receptor SKCaR in kidney of dogfish, Squalus acanthias

    Am. J. Physiol. Renal Physiol.

    (2003)
  • S. Chakrabarty et al.

    Extracellular calcium and calcium sensing receptor function in human colon carcinomas: promotion of E-cadherin expression and suppression of β-catenin/TCF activation

    Cancer Res.

    (2003)
  • E. Kallay et al.

    Dietary calcium and growth modulation of human colon cancer cells: role of the extracellular calcium-sensing receptor

    Cancer Detect. Prev.

    (2000)
  • Cited by (98)

    • Phenylalanine and tryptophan stimulate gastrin and somatostatin secretion and H<sup>+</sup>-K<sup>+</sup>-ATPase activity in pigs through calcium-sensing receptor

      2018, General and Comparative Endocrinology
      Citation Excerpt :

      These data suggest that CaSR plays a role in amino acid-induced gastrin and SS secretion and H+-K+-ATPase activity in swine. CaSR activation in the intact rat gastric glands increases gastric acid secretion rate through the apical H+-K+-ATPase (Geibel et al., 2001; Hebert et al., 2004). Busque et al. (2005) reported that the allosteric activation of CaSR by amino acids directly enhanced H+-K+-ATPase activity.

    View all citing articles on Scopus
    View full text