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Journal of Endocrinology (2008) 199, 1-4       DOI: 10.1677/JOE-08-0261
© 2008 Society for Endocrinology
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HYPOTHESIS

The calcium-sensing receptor and insulin secretion: a role outside systemic control 15 years on

 M N Hodgkin, C E Hills1 and P E Squires

Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, UK1 Department of Infection, Immunity and Inflammation, Leicester School of Medicine, University of Leicester, PO Box 138, Leicester LE1 7RH, UK

(Correspondence should be addressed to P E Squires; Email: p.e.squires{at}warwick.ac.uk)


   Abstract
Top
 Abstract
Introduction
 CaR: cell-to-cell communication...
 CaR: a role in...
 Conclusion
 Declaration of interest
 References
 
In the 15 years since the identification and characterisation of the extracellular calcium-sensing receptor (CaR), it has become increasingly apparent that this cationic binding receptor is found in many tissues, not associated with the control of plasma calcium. One of these tissues is the pancreatic islet where insulin secretion provides the basis of energy regulation. It seems inherently unlikely that the islet responds to alterations in systemic calcium and a more plausible and intriguing possibility is that the CaR mediates cell-to-cell communication through local increases in the concentration of extracellular Ca2+, co-released with insulin. This short article explores this possibility and suggests that this novel mechanism of cell communication, along with direct coupling via gap junctions and other local paracrine regulators helps explain why the glucose responsiveness of the intact islet is greater than the sum of the composite parts in isolation.


   Introduction
Top
 Abstract
 Introduction
CaR: cell-to-cell communication...
 CaR: a role in...
 Conclusion
 Declaration of interest
 References
 
It has been 15 years since the original cloning and characterisation of the extracellular calcium-sensing receptor (CaR; Brown et al. 1993). Since then more than 1000 articles have been published chronicling the role of this G protein-coupled receptor in the physiology and pathophysiology of systemic calcium regulation (extensively reviewed in Brown 2007). However, over the last decade and a half it has become apparent that the ability of cells to detect local changes in free calcium ion concentration is not restricted to tissues involved in Ca2+ homeostasis. The CaR has been detected in an ever increasing range of tissue types, including oesophageal (Justinich et al. 2008) and colonic epithelia (Cheng et al. 2004), the cardiovascular system (reviewed in Smajilovic & Tfelt-Hansen 2007), hypothalamic neurons (Vizard et al. 2008), pancreatic ducts (Racz et al. 2002) and pancreatic {alpha}- and β-cells (Rasschaert & Malaisse 1999, Squires et al. 2000, Gray et al. 2006).

The functional significance of the CaR in tissue not involved in regulating plasma Ca2+ is not fully understood. In the exocrine pancreas, it has been suggested that the CaR monitors extracellular Ca2+ in pancreatic juice to limit the risk of calcium carbonate stone formation (Bruce et al. 1999) and in gastrin-secreting cells of the human antrum the CaR may detect dietary Ca2+ (Ray et al. 1997, Buchan et al. 2001). However, a more global explanation for the role of the CaR in these disparate tissues could be in its ability to detect local fluctuations in Ca2+, mediating cell-to-cell communication and coupling function. Cells communicate locally via gap junctions that physically connect adjacent cells and permit the free flow of ions and small molecules (Hills et al. 2006), or through the release of local paracrine messengers (Squires et al. 2002). Recent evidence, from our work on pancreatic β-cells, suggests an important function for the CaR in mediating cell-to-cell communication within islets to coordinate insulin secretory responses (Jones et al. 2007). Local changes in the concentration of extracellular Ca2+ can occur as result of changes in Ca2+-influx/efflux pathways across the plasma membrane (Green et al. 2007). Additionally, secretory granules contain high concentrations of calcium that is released upon exocytosis (Belan et al. 1998). As the volume of space between cells is often small, large changes in Ca2+ concentration can occur in the micro-environment immediately surrounding cells (Perez-Armendariz & Atwater 1986). These local extracellular ‘hot-spots’ of calcium are sufficient to activate the CaR on neighbouring cells and facilitate cellular co-operation.


   CaR: cell-to-cell communication and the pancreatic islet
Top
 Abstract
 Introduction
 CaR: cell-to-cell communication...
CaR: a role in...
 Conclusion
 Declaration of interest
 References
 
Several theories have been proposed to explain the synchronous and cooperative activity of islets when compared with non-cooperative events in isolated individual β-cells including direct communication via gap junctions (Moreno et al. 2005, Rogers et al. 2007), the presence of other endocrine cells (Ishihara et al. 2003), as well as the existence of extracellular diffusible mediators (Squires et al. 2002, Hellman et al. 2004). The possibility that local changes in extracellular Ca2+, resulting from the efflux of mobilised Ca2+, in one cell are sufficient to activate the CaR on an adjacent cell was elegantly demonstrated in a HEK293 model system (Hofer et al. 2000). These studies suggested that the extrusion of Ca2+ from stimulated cells, recruited neighbouring cells, allowing amplification and integration of a tissue-wide response (reviewed in Hofer et al. 2004). In the pancreas, we have long argued that close cell-to-cell contact improves the functional responsiveness of cells and augments insulin secretion (Hauge-Evans et al. 1999). Activation of the CaR using receptor-specific calcimimetics (reviewed in Trivedi et al. 2008) enhances insulin secretion from human islets (Gray et al. 2006) and provides an obvious link by which glucose-evoked release of calcium-rich secretory granules feeds forward to synchronise secretion and perpetuate the whole islet response. The proposed model of this CaR-mediated propagation of signals across the islet is illustrated in the schematic below. Here, glucose-evoked changes in insulin secretion in one cell can stimulate insulin secretion from neighbouring cells expressing the CaR, through co-release of divalent cations, ultimately improving overall secretory function (Fig. 1).


Figure 1
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  		Figure 1 CaR-mediated cell-to-cell communication within pancreatic islets: glucose metabolism within pancreatic β-cells is limited by the low-affinity glucokinase (GK). The resultant rise in ATP/ADP ratio closes the ATP-sensitive potassium channels (K+ATP), depolarising the cell membrane and opening voltage-dependent Ca2+ channels (VDCC). Calcium enters the cell down a concentration gradient and stimulates insulin secretion (bullet). Divalent cations, including free Ca2+(°), are co-released with insulin, increasing the local concentration of extracellular calcium ({uparrow}[Ca2+]e) in the intra-islet space. These changes act in a paracrine fashion that is detected by the extracellular Ca2+-sensing receptor (CaR) on adjacent cells. CaR mediated increases in [Ca2+]i, propagate the signal across the islet, thus co-ordinating activity and enhancing glucose-induced insulin secretion.

 
It is unusual for receptor-mediated stimuli to initiate insulin release in the absence of stimulatory glucose concentrations. However, calcimimetic activation of the CaR in human and rodent β-cells transiently increases insulin secretion, without the need for an associated increase in nutrient stimulation (Gray et al. 2006), stressing the potential importance of the CaR to islet function. It is therefore surprising that activating mutations of the CaR as seen in autosomal-dominant hypocalcaemia (extensively reviewed in Egbuna & Brown 2008) cause hypocalcaemia of varying severity without hypoglycaemia as expected from an increase in insulin secretion under the current model. This discrepancy could be explained by the fact that hypocalcaemia has been shown to reduce insulin secretion (Schlumbohm & Harmeyer 2002), perhaps through a reduced drive for Ca2+ entry following glucose-stimulated closure of the ATP-sensitive potassium channels on the β-cells. Certainly, if CaR function is increased in pancreatic β-cells from a background of eucalcemia there is an increase in insulin secretion (Gray et al. 2006), an effect that may form the basis of the intra-arterial calcium stimulation test for the detection of insulinomas (Kato et al. 1997, Won et al. 2003). The loss of CaR function may partially explain increased prevalence of coincident diabetes in patients presenting with primary hyperparathyroidism, where the loss of CaR function in the parathyroid increases parathyroid hormone (PTH) secretion (reviewed in Taylor & Khaleeli 2001).


   CaR: a role in cell adhesion and proliferation in the islet
Top
 Abstract
 Introduction
 CaR: cell-to-cell communication...
 CaR: a role in...
Conclusion
 Declaration of interest
 References
 
The biosynthetic and secretory function of the islet depends largely on the architecture of the islet, itself dictated by specialised cell adhesion molecules such as the cell surface adhesion protein epithelial (E)-cadherin (ECAD) and β-catenin (reviewed in D'Souza-Schorey 2005). The co-localisation of adherens junction proteins to secretory granules (Hodgkin et al. 2007) suggests that the adherens junction may play a novel role in β-cell function, both in terms of β-cell proliferation (Carvell et al. 2007) and insulin secretion (Hodgkin et al. 2007, Rogers et al. 2007). Neutralising ECAD-mediated cell adhesion decreases glucose-evoked synchronicity in Ca2+ signals between adjacent cells within islets (Rogers et al. 2007) and evidence from human epidermal keratinocytes suggests that inactivation of the CaR suppresses the assembly of the ECAD–catenin–phosphotidylinositol 3–kinase (PI3K) complex (Tu et al. 2008). These data provide compelling evidence that the CaR influences multiple functions that ultimately regulate synchronicity of Ca2+ activity between β-cells within the islet and thus dramatically impinge on insulin secretion.


   Conclusion
Top
 Abstract
 Introduction
 CaR: cell-to-cell communication...
 CaR: a role in...
 Conclusion
Declaration of interest
 References
 
Calcium receptor-mediated cell-to-cell communication permits local changes in co-released Ca2+ to synchronise whole islet responses to secretagogues. It seems likely that the local paracrine function of extracellular Ca2+ acts in unison with other better characterised mechanisms for cellular coupling, to ensure appropriate glucose responsiveness. Calcimimetic compounds that activate the CaR and block PTH secretion have been developed to treat hyperparathyroidism, while calcilytic compounds potentially provide an anabolic therapy for osteoporosis (reviewed in Nemeth 2004). However, the expression of a functional CaR within human pancreatic islets suggests that these therapies may have wider implications for tissues outside the normal targets for control of systemic calcium, and these possible contraindications need to be fully explored. This short article demonstrates the importance of the CaR in orchestrating a synchronised whole islet response to improve secretory function.


   Declaration of interest
Top
 Abstract
 Introduction
 CaR: cell-to-cell communication...
 CaR: a role in...
 Conclusion
 Declaration of interest
References
 
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.


   Funding
 
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.


   References
Top
 Abstract
 Introduction
 CaR: cell-to-cell communication...
 CaR: a role in...
 Conclusion
 Declaration of interest
 References
 
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Received in final form 12 June 2008
Accepted 23 June 2008
Made available online as an Accepted Preprint 24 June 2008





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