ABSTRACT
The Calcium-Sensing Receptor (CaSR) is a member of the class C of G-proteins coupled receptors (GPCRs), it plays a pivotal role in calcium homeostasis by directly controlling calcium excretion in the kidneys and indirectly by regulating parathyroid hormone (PTH) release from the parathyroid glands. The CaSR is found to be ubiquitously expressed in the body, playing a plethora of additional functions spanning from fluid secretion, insulin release, neuronal development, vessel tone to cell proliferation and apoptosis, to name but a few. The present review aims to elucidate and clarify the emerging regulatory effects that the CaSR plays in inflammation in several tissues, where it mostly promotes pro-inflammatory responses, with the exception of the large intestine, where contradictory roles have been recently reported. The CaSR has been found to be expressed even in immune cells, where it stimulates immune response and chemokinesis. On the other hand, CaSR expression seems to be boosted under inflammatory stimulus, in particular, by pro-inflammatory cytokines. Because of this, the CaSR has been addressed as a key factor responsible for hypocalcemia and low levels of PTH that are commonly found in critically ill patients under sepsis or after burn injury. Moreover, the CaSR has been found to be implicated in autoimmune-hypoparathyroidism, recently found also in patients treated with immune-checkpoint inhibitors. Given the tight bound between the CaSR, calcium and vitamin D metabolism, we also speculate about their roles in the pathogenesis of severe acute respiratory syndrome coronavirus-19 (SARS-COVID-19) infection and their impact on patients' prognosis. We will further explore the therapeutic potential of pharmacological targeting of the CaSR for the treatment and management of aberrant inflammatory responses.
ABSTRACT
Over the recent decades, a number of new pathogens have emerged within specific and diverse populations across the globe, namely, the Nipah virus, the Ebola virus, the Zika virus, and coronaviruses (CoVs) to name a few. Recently, a new form of coronavirus was identified in the city of Wuhan, China. Interestingly, the genomic architecture of the virus did not match with any of the existing genomic sequencing data of previously sequenced CoVs. This had led scientists to confirm the emergence of a new CoV strain. Originally, named as 2019-nCoV, the strain is now called as SARS-CoV-2. High serum levels of proinflammatory mediators, namely, interleukin-12 (IL-12), IL-1ß, IL-6, interferon-gamma (IFNγ), chemoattractant protein-1, and IFN-inducible protein, have been repeatedly observed in subjects who were infected with this virus. In addition, the virus demonstrated strong coagulation activation properties, leading to further the understanding on the SARS-CoV2. To our understanding, these findings are unique to the published literature. Numerous studies have reported anomalies, namely, decline in the number of lymphocytes, platelets and albumins; and a rise in neutrophil count, aspartate transaminase, alanine aminotransaminase, lactate dehydrogenase, troponins, creatinine, complete bilirubin, D-dimers, and procalcitonin. Supplementation of calcium during the SARS CoV-2 associated hyperactive stage of calcium-sensing receptors (CaSR) may be harmful to the cardio-renal system. Thus, pharmacological inhibition of CaSR may prevent the increase in the levels of intracellular calcium, oxidative, inflammatory stress, and cardio-renal cellular apoptosis induced by high cytokines level in COVID-19 infection.