Editorial [Hot Topic:The Calcium-Sensing Receptor: Pathophysiology and Pharmacological Modulation(Guest Editor: Ubaldo Armato)]

Being one of the most abundant cations in nature, calcium plays crucial roles both outside and inside the cells as a signaling ion. Changes in the extracellular free calcium concentration [Ca2+ o] activate the plasmalemmal calcium-sensing receptor (CaSR or CaR), a sevenfold transmembrane spanning protein encoded by genes mapped in human chromosome 3 (and also 19). The CaSR is activated by various ligands, such as divalent and polyvalent cations, aromatic L-amino acids, aminoglycosides, spermine, and amyloid β (Aβ) peptides. A member of family C (or III) of G-protein coupled receptors (GPCRs), acting in the form of a disulfide-linked homodimer, the CaSR signals through both heterotrimeric and monomeric G-proteins, thereby inhibiting adenylate cyclase activity, but increasing the production of diacylglycerol (DAG) and inosiltol-1,4,5-triphosphate (IP3), mobilizing intracellular calcium, activating diverse protein kinases (PKB, PKCs, MAPKs), phospholipases (A2, C, D) and cyclooxygenase-2 (COX-2), and transactivating the EGF receptor (EGFR). CaSR signaling controls mineral ion homeostasis via parathyroid hormone (PTH) and calcitonin (CT) secretion and, in addition, modulates a variety of vital processes including chemotaxis, cell proliferation, differentiation, and malignant transformation, membrane excitability, cell survival, and programmed death (apoptosis). Notably, the expression of CaSR mRNA is widespread, occurring not only in the thyroid and the parathyroid glands (where it was first discovered), but even in kidney, bone, cardiovascular system, liver, gastrointestinal tract, and central nervous system (CNS). This broad expression implies multiple relevant functional roles for the CaSR in the same tissues and organs, the elucidation of which is still ongoing, being somewhat hampered by the facts that (i) not all of the CaSR-expressing cell types (e.g. in the CNS) have hitherto been identified with certainty, and (ii) in each cell-type considered the CaSR-evoked responses to [Ca2+ o] changes exhibit a discrete degree of specificity. It goes without saying that, given this background, in pathologic conditions the CaSR also plays relevant roles, most of which however wait to be clarified. Besides hereditary conditions due to loss-of-function or gain-of-function mutations and polymorphisms of the CaSR, several pathophysiological conditions associated with local and/or general reductions in the [Ca2+ o], oxidative stress and/or extracellular acidification appear to elicit significant changes in CaSR signaling. Therefore, a panoply of agents targeting the CaSR, both calcimimetics (or calcium agonists) and calcilytics (or calcium antagonists), is being developed and tested in specific clinical settings. Accordingly, the CaSR has now fittingly become an exciting topic of the impetuously growing Translational Medicine. This has led to the proposal of collecting in the present issue the reviews from several research groups with the aim of bringing up to date, from different viewpoints, novel facets of the several CaSR roles and the known or possible benefits of the CaSR-targeting drugs concerning the pathophysiology of the the cardiovascular system, bone, kidney, colon, and CNS. The first review of this series, contributed by Drs. Brennan and Conigrave, enlightens the quite intricate CaSR's signaling cascades, which change membrane lipids metabolism, several protein kinases’ activities and their substrates' phosphorylation, and intracellular cAMP, calcium ions and fatty acids levels via G-proteins’ activations. Thus, consistent with its expression site(s) and local signaling pathways, CaSR responses to changes in [Ca2+ o] modulate vital cell activities including, amongst others, peptide hormone secretion, vitamin D metabolism, and ion and water transport. This updated information also underscores the need of further studies to better clarify the intricate yet enticing CaSR signaling mechanisms.