Abstract
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.
Highlights
The calcium sensing receptor (CaSR) is a member of family C G-protein coupled receptors (GPCRs), and it was first cloned from bovine parathyroid gland in 1993 [1]
The patch-clamp of rat hippocampal neurons demonstrated that the activation of the CaSR with high extracellular Ca2+, neomycin, or spermine significantly increased the opening state probability of nonselective cation channels in WT neurons but not in cells isolated from CaR-/- mice [63,64]
By highlighting the importance of family C GPCRs dimerization, these studies added a further level of complexity in elucidating the role of the CaSR in the brain and raised questions regarding (i) how these interactions between GPCRs might affect ligand binding and sensitivity; (ii) what might be the biological meaning of such dimerization in the nervous system; (iii) how dimerization affects the pharmacology of the resulting receptor; and (iv) how dimerization modulates the signaling networks and neurotransmission
Summary
The calcium sensing receptor (CaSR) is a member of family C G-protein coupled receptors (GPCRs), and it was first cloned from bovine parathyroid gland in 1993 [1]. To negatively regulate PTH secretion from parathyroid cells, the CaSR operates through the Gi/o-mediated inhibition of adenylate cyclase, which suppresses cAMP intracellular synthesis and the consequent release of parathyroid hormone [27,28]. Studies suggest that the CaSR supports the chemotaxis of osteoblast precursors to the site of resorption via calcium gradients [34], while it mediates the migration of immune cells through the PLC pathway [35]. Such evidences are in line with the CaSR biased signaling and strongly highlight the diversity of the receptor-mediated processes. (iii) describe the potential use of CaSR-based therapeutics in disorders such as ischemia, Alzheimer’s disease and neuroblastoma; and (iv) propose alternative strategies to further investigate critical and unsolved issues regarding the receptor’s function and signaling in the nervous system
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