The Extracellular Calcium-Sensing Receptor in the Intestine: Evidence for Regulation of Colonic Absorption, Secretion, Motility, and Immunity

Abstract

Different from other epithelia, the intestinal epithelium has the complex task of providing a barrier impeding the entry of toxins, food antigens, and microbes, while at the same time allowing for the transfer of nutrients, electrolytes, water, and microbial metabolites. These molecules/organisms are transported either transcellularly, crossing the apical and basolateral membranes of enterocytes, or paracellularly, passing through the space between enterocytes. Accordingly, the intestinal epithelium can affect energy metabolism, fluid balance, as well as immune response and tolerance. To help accomplish these complex tasks, the intestinal epithelium has evolved many sensing receptor mechanisms. Yet, their roles and functions are only now beginning to be elucidated. This article explores one such sensing receptor mechanism, carried out by the extracellular calcium-sensing receptor (CaSR). In addition to its established function as a nutrient sensor, coordinating food digestion, nutrient absorption, and regulating energy metabolism, we present evidence for the emerging role of CaSR in the control of intestinal fluid homeostasis and immune balance. An additional role in the modulation of the enteric nerve activity and motility is also discussed. Clearly, CaSR has profound effects on many aspects of intestinal function. Nevertheless, more work is needed to fully understand all functions of CaSR in the intestine, including detailed mechanisms of action and specific pathways involved. Considering the essential roles CaSR plays in gastrointestinal physiology and immunology, research may lead to a translational opportunity for the development of novel therapies that are based on CaSR's unique property of using simple nutrients such as calcium, polyamines, and certain amino acids/oligopeptides as activators. It is possible that, through targeting of intestinal CaSR with a combination of specific nutrients, oral solutions that are both inexpensive and practical may be developed to help in conditioning the gut microenvironment and in maintaining digestive health.

Keywords: calcium-sensing receptor; enteric nervous system; gut immunity; inflammatory bowel disease; intestinal barrier function; irritable bowel syndrome; motility; secretory diarrhea.

Figure 1

Schematic diagram illustrating pathways and mechanisms through which CaSR-activating calcimimetics and agonists modulate GI physiology and immunophysiology. Known CaSR effects include: (A) increased absorption, (B) decreased secretion, (C) enhanced intestinal barrier and reduced inflammation, and (D) reduced enteric nerve activity and motility (see text for explanations). CaSR, calcium-sensing receptor; CFTR, cystic fibrosis transmembrane conductance regulator; PDE, phosphodiesterase; SCFA, short-chain fatty acid; VIP, vasoactive intestinal peptide; +, stimulation; –, inhibition.

Figure 2

Schematic representation of the colonocytes showing how deficiency in intestinal CaSR results in increased gut permeability and inflammation. Central panel, illustrates a current model of self-amplifying pathway for intestinal disease (Turner, 2006) where a small amount of luminal bacteria or bacteria-derived molecules pass across the epithelium to activate lamina propria immune cells, leading to secretion of proinflammatory cytokines (e.g., TNFα) and subsequent activation of their receptors (e.g., TNFR) in the epithelium. The latter increases MLCK transcription and activity and phosphorylation of myosin light chain (MLC), resulting in increased contractility of perijunctional actin-myosin ring and increased epithelial permeability. The consequences are greater access leakage of luminal materials, greater immune activation, and even greater barrier defects. The presence of CaSR ligands and signals limits amplifying of this cascade through activation of phosphodiesterase (PDE) (Geibel et al., 2006) and inhibition of MLCK (Cheng et al., 2014), leading to MLC dephosphorylation and barrier stabilization. Thus, in the presence of intact CaSR signaling, as in CaSR^+∕+ mice, immune tolerance or only low-grade inflammation is seen (Right panel). However, in the absence of CaSR signal, as in CaSR^−∕− mice, the limiting of this cascade amplification is lost, leading to immune activation and uncontrolled inflammation (Macleod, ; Cheng et al., 2014) (Left panel).