scholarly journals The Nervous System Relevance of the Calcium Sensing Receptor in Health and Disease

Molecules ◽  
2019 ◽  
Vol 24 (14) ◽  
pp. 2546 ◽  
Author(s):  
Maria Lo Giudice ◽  
Balázs Mihalik ◽  
András Dinnyés ◽  
Julianna Kobolák
Keyword(s):  
Nervous System ◽  
Calcium Homeostasis ◽  
Neural Development ◽  
Primary Role ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Physiological Processes ◽  
Receptor Inhibition ◽  
Neuroblastic Tumors ◽  
Health And Disease

The calcium sensing receptor (CaSR) was first identified in parathyroid glands, and its primary role in controlling systemic calcium homeostasis by the regulation of parathyroid hormone (PTH) secretion has been extensively described in literature. Additionally, the receptor has also been investigated in cells and tissues not directly involved in calcium homeostasis, e.g., the nervous system (NS), where it plays crucial roles in early neural development for the differentiation of neurons and glial cells, as well as in the adult nervous system for synaptic transmission and plasticity. Advances in the knowledge of the CaSR’s function in such physiological processes have encouraged researchers to further broaden the receptor’s investigation in the neuro-pathological conditions of the NS. Interestingly, pre-clinical data suggest that receptor inhibition by calcilytics might be effective in counteracting the pathomechanism underlying Alzheimer’s disease and ischemia, while a CaSR positive modulation with calcimimetics has been proposed as a potential approach for treating neuroblastoma. Importantly, such promising findings led to the repurposing of CaSR modulators as novel pharmacological alternatives for these disorders. Therefore, the aim of this review article is to critically appraise evidence which, so far, has been yielded from the investigation of the role of the CaSR in physiology of the nervous system and to focus on the most recent emerging concepts which have reported the receptor as a therapeutic target for neurodegeneration and neuroblastic tumors.

scholarly journals The Calcium Sensing Receptor: From Understanding Parathyroid Calcium Homeostasis to Bone Metastases

2008 ◽  
Vol 90 (4) ◽  
pp. 271-277 ◽  
Author(s):  
Radu Mihai
Keyword(s):  
Breast Cancer ◽  
Bone Metastases ◽  
Intracellular Calcium ◽  
Calcium Homeostasis ◽  
Membrane Trafficking ◽  
Calcium Concentration ◽  
Fluorescent Microscopy ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Parathyroid Adenomas

The cloning of the calcium sensing receptor (CaR) confirmed that parathyroid cells monitor extracellular calcium concentration ([Ca2+]ext) via a receptor-type mechanism. This lead to the hypothesis that abnormalities in the expression and/or function of the CaR could explain the biochemical abnormalities in primary hyperparathyroidism (PHPT). Cultured cells from parathyroid adenomas of patients operated for PHPT were used to monitor real-time changes in intracellular calcium concentration ([Ca2+]i) as measured by fluorescent microscopy using the Fura-2/AM dye. We found that CaR agonists trigger release of intracellular calcium pools and such responses are amplified by increasing the affinity of IP3 receptors. Using confocal microscopy to monitor membrane trafficking in living parathyroid cells labelled with the fluorescent dye FM1-43, we found that a decrease in [Ca2+]i rather than an absolute change in [Ca2+]ext is the main stimulus for exocytosis from human parathyroid cells. These data suggest that, in PHPT, a defective signalling mechanism from the CaR allows cells from parathyroid adenomas to maintain low [Ca2+]i with uninhibited PTH secretion in the face of hypercalcaemia. Over longer periods of time, CaR controls parathyroid proliferation via changes in tyrosine phosphorylation. We found that multiple proteins of molecular weight 20–65 kDa are phosphorylated within 10–60 min in response to CaR agonists. Further work demonstrated that high [Ca2+]i stimulates the expression of bcl-2 oncoprotein in cultured human parathyroid cells and that, in parathyroid adenomas, predominant expression of bcl-2 rather than bax oncoprotein might prevent apoptosis and explain the slow growth rate of these tumours. More recently, it became apparent that CaR stimulates cell proliferation in several cell types not involved in calcium homeostasis. Using archived histological material from 65 patients who died with metastatic breast cancer, we identified CaR expression predominantly in tumours from patients who developed bone rather than visceral metastases (35 of 49 versus 7 of 16; P < 0.01, chi-squared test). These data suggest that CaR expression has the potential to become a new biological marker predicting the risk of bone metastases in patients with breast cancer. A prospective study should investigate if patients with CaR-positive tumours are more likely to develop bone metastases and whether they could benefit more from prophylactic treatment with bisphosphonates or the newly developed CaR antagonists.

The Calcium-Sensing Receptor in Health and Disease

2016 ◽  
pp. 321-369 ◽  
Author(s):  
G. Díaz-Soto ◽  
A. Rocher ◽  
C. García-Rodríguez ◽  
L. Núñez ◽  
C. Villalobos
Keyword(s):  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Health And Disease

scholarly journals Calcium-sensing receptor inhibits secretagogue-induced electrolyte secretion by intestine via the enteric nervous system

2012 ◽  
Vol 303 (1) ◽  
pp. G60-G70 ◽  
Author(s):  
Sam X. Cheng
Keyword(s):  
Nervous System ◽  
Cyclic Amp ◽  
Enteric Nervous System ◽  
Cyclic Nucleotide ◽  
Short Circuit ◽  
Significant Proportion ◽  
Rat Colon ◽  
Inhibitory Effects ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

Bacterial toxins such as cholera toxin induce diarrhea by both direct epithelial cell generation of cyclic nucleotides as well as stimulation of the enteric nervous system (ENS). Agonists of the extracellular calcium-sensing receptor (CaSR) can reduce toxin-stimulated fluid secretion in ENS-absent colonic epithelial crypts by increasing phosphodiesterase-dependent cyclic-nucleotide degradation. Here we show that the CaSR is also highly expressed in tetrodotoxin (TTX)-sensitive neurons comprising the ENS, suggesting that CaSR agonists might also function through neuronal pathways. To test this hypothesis, rat colon segments containing intact ENS were isolated and mounted on Ussing chambers. Basal and cyclic nucleotide-stimulated electrolyte secretions were monitored by measuring changes in short-circuit current ( Isc). CaSR was activated by R-568 and its effects were compared in the presence and absence of TTX. Consistent with active regulation of anion secretion by the ENS, a significant proportion of Isc in the proximal and distal colon was inhibited by serosal TTX, both at basal and under cyclic AMP-stimulated conditions. In the absence of TTX, activation of CaSR with R-568 significantly reduced basal Isc and cyclic AMP-stimulated Isc; it also completely reversed the cAMP-stimulated secretory responses if the drug was applied after the forskolin stimulation. Such inhibitory effects of R-568 were either absent or significantly reduced when serosal TTX was present, suggesting that this agonist exerts its antisecretory effect on the intestine by inhibiting ENS. The present results suggest a new model for regulating intestinal fluid transport in which neuronal and nonneuronal secretagogue actions are modulated by the inhibitory effects of CaSR on the ENS. The ability of a CaSR agonist to reduce secretagogue-stimulated Cl− secretion might provide a new therapeutic approach for secretory and other ENS-mediated diarrheal conditions.

scholarly journals Diverse roles of extracellular calcium-sensing receptor in the central nervous system

2010 ◽  
Vol 88 (10) ◽  
pp. 2073-2082 ◽  
Author(s):  
Sanghamitra Bandyopadhyay ◽  
Jacob Tfelt-Hansen ◽  
Naibedya Chattopadhyay
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Extracellular Calcium ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
The Central Nervous System
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