-The extracellular calcium-sensing receptor CaSR is expressed in blood vessels where its role is not completely understood. In this study, we tested the hypothesis that the CaSR expressed in vascular smooth muscle cells (VSMC) is directly involved in regulation of blood pressure and blood vessel tone. Mice with targeted CaSR gene ablation from vascular smooth muscle cells (VSMC) were generated by breeding exon 7 LoxP-CaSR mice with animals in which Cre recombinase is driven by a SM22␣ promoter (SM22␣-Cre). Wire myography performed on Cre-negative [wild-type (WT)] and Crepositive SM22␣ CaSR ⌬flox/⌬flox [knockout (KO)] mice showed an endothelium-independent reduction in aorta and mesenteric artery contractility of KO compared with WT mice in response to KCl and to phenylephrine. Increasing extracellular calcium ion (Ca 2ϩ ) concentrations (1-5 mM) evoked contraction in WT but only relaxation in KO aortas. Accordingly, diastolic and mean arterial blood pressures of KO animals were significantly reduced compared with WT, as measured by both tail cuff and radiotelemetry. This hypotension was mostly pronounced during the animals' active phase and was not rescued by either nitric oxide-synthase inhibition with nitro-L-arginine methyl ester or by a high-salt-supplemented diet. KO animals also exhibited cardiac remodeling, bradycardia, and reduced spontaneous activity in isolated hearts and cardiomyocyte-like cells. Our findings demonstrate a role for CaSR in the cardiovascular system and suggest that physiologically relevant changes in extracellular Ca 2ϩ concentrations could contribute to setting blood vessel tone levels and heart rate by directly acting on the cardiovascular CaSR. calcium-sensing receptor; CaSR; vascular smooth muscle cells; blood pressure regulation; G protein-coupled receptor; blood vessel tone regulation THE EXTRACELLULAR CALCIUM -sensing receptor CaSR was the first G protein-coupled receptor identified that has an ion, Ca 2ϩ

The calcimimetic-dependent increase in biosynthesis and activation of the CaSR in h-VSMCs probably play a key role in the protection against calcium-induced VC.

Daniela Riccardi has always been fascinated with how cells sense changes in their environment and their responses at the molecular and cellular through to whole-organism level. The extracellular calcium-sensing receptor (CaSR) has the unique ability to sample the extracellular milieu and to integrate multiple stimuli into one output, in a manner that is both cell and signal dependent. In most cases this feature is a boon, but it can become a bane when non-physiological CaSR activators hijack this receptor, leading to CaSR overactivation, hence pathology. Since receiving the Wellcome Trust Prize for Excellence in Physiology in 2000, Daniela Riccardi's work has focused on elucidating the physiological roles of the CaSR in non-calciotrophic tissues, on the identification of tissue-specific physiopathological stimuli and on the use of pharmacological modulators of the CaSR to manipulate receptor function in diseases such as vascular calcification and asthma. New Findings r What is the topic of this review?The extracellular calcium-sensing receptor, CaSR, ensures whole-body Ca 2+ homeostasis. Recent developments highlight the importance of the CaSR beyond mineral ion metabolism. This review focuses on novel roles and the use of CaSR-based therapeutics within the vasculature, the gut and the lung. r What advances does it highlight?The ability of the CaSR to act as a multimodal chemosensor has led to the identification of signalling pathways that are ligand and cellular context dependent. Development of cell-specific CaSR modulators is now being harnessed to rescue aberrant CaSR function outside the extracellular Ca 2+ homeostatic system.The extracellular calcium-sensing receptor, CaSR, is the first G protein-coupled receptor found to have an inorganic ion, calcium (Ca 2+ ), as its physiological agonist. It is highly expressed in all organs involved in the regulation of mineral ion metabolism, namely the parathyroid gland, the kidney and bone. The CaSR is the master controller of extracellular Ca 2+ concentration, as highlighted by the evidence that both inherited and acquired mutations in the CASR gene cause disturbances in mineral ion metabolism. CaSR positive allosteric modulators have been successfully employed in the clinic for over a decade to restore CaSR function, which is reduced in hyperparathyroidism secondary to kidney failure, while negative allosteric modulators are currently being tested in patients with hypocalcaemia with hypercalciuria due to gain-of-function CASR mutations. In addition to its expression within the bone-kidney-parathyroid axis, the CaSR can be found in other tissues, including but not limited to the gut, the vasculature and the lung. Here, the CaSR acts as a chemosensor, integrating signals deriving from nutrient availability, salinity, acidification and the presence of ubiquitous polyamines. Knowledge of what these stimuli are and of the cell-specific signalling responses they evoke is crucial to our understanding of the non-calciotropic roles of the CaSR in physiology and how these a...

BackgroundImpaired mineral ion metabolism is a hallmark of CKD–metabolic bone disorder. It can lead to pathologic vascular calcification and is associated with an increased risk of cardiovascular mortality. Loss of calcium-sensing receptor (CaSR) expression in vascular smooth muscle cells exacerbates vascular calcification in vitro. Conversely, vascular calcification can be reduced by calcimimetics, which function as allosteric activators of CaSR.MethodsTo determine the role of the CaSR in vascular calcification, we characterized mice with targeted Casr gene knockout in vascular smooth muscle cells (SM22αCaSRΔflox/Δflox).ResultsVascular smooth muscle cells cultured from the knockout (KO) mice calcified more readily than those from control (wild-type) mice in vitro. However, mice did not show ectopic calcifications in vivo but they did display a profound mineral ion imbalance. Specifically, KO mice exhibited hypercalcemia, hypercalciuria, hyperphosphaturia, and osteopenia, with elevated circulating fibroblast growth factor 23 (FGF23), calcitriol (1,25-D3), and parathyroid hormone levels. Renal tubular α-Klotho protein expression was increased in KO mice but vascular α-Klotho protein expression was not. Altered CaSR expression in the kidney or the parathyroid glands could not account for the observed phenotype of the KO mice.ConclusionsThese results suggest that, in addition to CaSR’s established role in the parathyroid-kidney-bone axis, expression of CaSR in vascular smooth muscle cells directly contributes to total body mineral ion homeostasis.