Best Practice & Research Clinical Endocrinology & Metabolism
5Control of renal calcium, phosphate, Electrolyte, and water excretion by the calcium-sensing receptor
Introduction
The calcium-sensing receptor (CaSR), a G protein-coupled receptor, is best known and understood for its control of PTH synthesis and secretion in response to changes in Ca2+o, but it also has prominent, tubule-specific effects in the kidney (Fig. 1).1, 2 CaSR activation in the kidney results in a marked diuresis of water, Ca2+ and salts that can reach the point of volume depletion and hypotension. These effects are in contrast to those of other G protein-coupled receptors along the nephron (e.g., AT1, V1, eicosanoid receptors) that also act via Gαi and Gαq but either have a minimal effect on volume or cause volume retention. Some of the effects of the CaSR in the kidney appear to affect Ca2+ and PO4 metabolism by antagonizing the effects of PTH on tubular transport of these ions, but the major renal effects of the CaSR are through direct effects on the renal tubular transport of Ca2+, Mg2+, Na+, K+, Cl−, H+, and H2O. Activation of the CaSR (hypercalcemia or mutations) reduces distal nephron reabsorption of Na+, K+, Cl−, and H2O. The expression of the CaSR along the nephron, in the gills of fish, and in the GI tract of aquatic animals that regulate body solute content indicates that it may have a physiologic role in the control of NaCl transport in addition to regulating Ca2+ and Mg2+ transport.3, 4 In land mammals, increased salt and water excretion may be tied to hypercalcemia and resultant increases in Ca2+ excretion in order to prevent the occurrence of high concentrations of Ca2+ in the urine with the accompanying risk of precipitation, nephrocalcinosis, and stone formation.
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Human studies
The role of the CaSR in human physiology has been demonstrated in studies of loss- and gain-of-function CaSR mutations, and in studies employing agents that increase or inhibit CaSR activity.
Physiological and pharmacological regulators of CaSR activity
Divalent cations activate the CaSR in the low millimolar range i.e., at physiologically relevant concentrations.23 The CaSR may, in fact, respond to the sum of polycations in its local environment rather than extracellular Ca2+ concentration alone.23
The CaSR can signal in a paracrine manner, possibly similar to that of purinergic receptors.24 Intracellular Ca2+ rises and then falls following receptor-mediated activation of many cell-signaling systems. The fall occurs in part because Ca2+ is
Expression pattern of the CaSR along the nephron and segment-specific transport functions
A significant limitation in studies of CaSR function in the kidney has arisen from the difficulty of clearly defining the patterns of CaSR expression along the nephron. Although all studies agree that the CaSR is expressed along the basolateral membrane of the thick ascending limb of Henle, a key site of regulated calcium reabsorption (Fig. 1),28, *29, *30, 31, 32, 33 different groups have reached different conclusions regarding the nature and level of CaSR expression in other sites despite the
Conclusion
The kidney is an essential component of the system that regulates body Ca2+ metabolism, and it does so by controlling urinary Ca2+ excretion. The clinical importance of the CaSR in the kidney relates to its responsibility not only for regulating whole body Ca2+ balance, but also for maintaining the solubility of Ca2+ in the urine and reducing the risk of nephrolithiasis. Hypercalciuria is the most common finding in patients with nephrolithiasis. Hypercalciuria may originate from increases in
Acknowledgements
This work was supported by a grant from the National Institutes of Health (DK-59985) to R.T. Miller, a VA Merit Review to R. T. Miller, the U. T. Southwestern O’Brien Center for Kidney Disease, and the Charles and Jane Pak Center of Mineral Metabolism and Clinical Research.
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Cited by (30)
Structural mechanism of cooperative regulation of calcium-sensing receptor-mediated cellular signaling
2020, Current Opinion in PhysiologyCitation Excerpt :A narrow concentration range of PO43− (∼0.8−1.5 mM) coupled with regulation of fibroblast growth factor 23 (FGF23) has been shown to directly impact parathyroid mineral metabolism [45,46]. Both FGF23 and CaSR are associated with Ca2+, Mg2+, and phosphate homeostasis, and are related to dysfunction in FHH, ADH and chronic kidney disease [47,48]. Recent work by Ward et al. directly characterized the mechanism of phosphate-induced parathyroid hormone secretion.
Biology of the extracellular calcium-sensing receptor
2019, Principles of Bone BiologyThe Calcium-Sensing Receptor and Vitamin D
2018, Vitamin D: Fourth EditionEnhanced expression of the calcium-sensing receptor in reactive astrocytes following ischemic injury in vivo and in vitro
2016, Journal of the Neurological SciencesCitation Excerpt :Astrocytes enhance tissue viability by regulating glutamate homeostasis, ion homeostasis (e.g., extracellular potassium buffering), water balance, and cerebral blood flow [43–45]. Considering that CaSR can be activated by various stimuli, including polyvalent cations and changes in pH and ionic strength [46–48], CaSR expression in reactive astrocytes may be modulated by temporal alterations in the extracellular ionic environment caused by ischemic injury; this may affect the extracellular ionic milieu and neuronal and glial viability. In support of this notion, CaSR is functionally expressed in human astrocytes and astrocytoma cell lines and may be involved in local ionic homeostasis within the brain via their capacity to regulate ion channels [9,13,14,49].
Differential expression of the calcium-sensing receptor in the ischemic and border zones after transient focal cerebral ischemia in rats
2015, Journal of Chemical NeuroanatomyCitation Excerpt :Although our data provides evidence that CaSR may be involved in the pathogenesis of ischemic stroke, the present study has limitations since it used transient models restricted to relatively short time windows, in order to avoid risks of fatal edema and hemorrhage (see as reviews Bahjat et al., 2013; Fisher et al., 2009; Macrae, 2011). Recent studies suggest that CaSR cannot only be activated by extracellular calcium but also by various stimuli, such as polyvalent cations, pH, and ionic strength (Riccardi et al., 2009; Sun and Murphy, 2010; Tyler Miller, 2013). Astrocytes contribute to cell survival in the ischemic penumbra during stroke, where astrocytes are involved in a number of activities that profoundly influence tissue viability during ischemia, including glutamate homeostasis, ion homeostasis (i.e., buffering of extracellular potassium), water balance, and cerebral blood flow regulation (Chen and Swanson, 2003; Kimelberg and Nedergaard, 2010; Zhao and Rempe, 2010).
Acute Management of Hypercalcemia
2015, The Parathyroids: Basic and Clinical Concepts: Third Edition