Signaling Through the Extracellular Calcium-Sensing Receptor (CaSR)

Abstract

The extracellular calcium ([Formula: see text])-sensing receptor (CaSR) was the first GPCR identified whose principal physiological ligand is an ion, namely extracellular Ca(2+). It maintains the near constancy of [Formula: see text] that complex organisms require to ensure normal cellular function. A wealth of information has accumulated over the past two decades about the CaSR's structure and function, its role in diseases and CaSR-based therapeutics. This review briefly describes the CaSR and key features of its structure and function, then discusses the extracellular signals modulating its activity, provides an overview of the intracellular signaling pathways that it controls, and, finally, briefly describes CaSR signaling both in tissues participating in [Formula: see text] homeostasis as well as those that do not. Factors controlling CaSR signaling include various factors affecting the expression of the CaSR gene as well as modulation of its trafficking to and from the cell surface. The dimeric cell surface CaSR, in turn, links to various heterotrimeric and small molecular weight G proteins to regulate intracellular second messengers, lipid kinases, various protein kinases, and transcription factors that are part of the machinery enabling the receptor to modulate the functions of the wide variety of cells in which it is expressed. CaSR signaling is impacted by its interactions with several binding partners in addition to signaling elements per se (i.e., G proteins), including filamin-A and caveolin-1. These latter two proteins act as scaffolds that bind signaling components and other key cellular elements (e.g., the cytoskeleton). Thus CaSR signaling likely does not take place randomly throughout the cell, but is compartmentalized and organized so as to facilitate the interaction of the receptor with its various signaling pathways.

Calcium Promotes Human Gastric Cancer via a Novel Coupling of Calcium-Sensing Receptor and TRPV4 Channel

“…Calcium and CaSR have been reported to either suppress or promote cancer depending on tumor types (7,24,25), and the aberrance in CaSR function in gastric cancer cells was also evident in the AKT/b-catenin pathway, which was enhanced in gastric cancer cells but suppressed in normal cells. Thus, CaSR activation only stimulated proliferation, growth, migration, and invasion of gastric cancer, but not normal cells.…”

“…CaSR activation stimulates [Ca 2þ ] cyt rise, as well as PI3K/AKT, b-catenin, and MAPK signaling (5,21,23,24), all of which are involved in malignant progression of cancers. Ca 2þ signaling is well recognized to regulate proliferation, migration, epithelial mesenchymal transition (EMT), and malignant transformation (22,26 (29).…”

Activation of the calcium-sensing receptor induces deposition of tight junction components to the epithelial cell plasma membrane

“…The CaSR was first identified in tissues and cells implicated in Ca 2+ homeostasis, including the parathyroid glands and the kidney (Brown et al, 1993;Tfelt-Hansen and Brown, 2005;Chakravarti et al, 2012;Geibel, 2010). Recent observations have demonstrated that the CaSR regulates the expression and distribution of members of the claudin (CLDN) family (Ikari et al, 2008;Gong et al, 2012).…”

“…By sensing minute variations of the extracellular Ca 2+ concentration ([Ca 2+ ] e ) and appropriately modulating the cellular responses to these changes, the CaSR plays an essential role in Ca 2+ homeostasis. Hence, it controls parathyroid hormone (PTH) secretion by the parathyroid glands and modulates Ca 2+ fluxes in the kidney and the bone (Chakravarti et al, 2012;Geibel, 2010). Mutations in the CASR gene have been associated with inherited disorders of divalent mineral homeostasis Hannan et al, 2012).…”

Healthful Eating, the Western Style Diet and Chronic Disease

“…Underlying mechanisms are not fully understood, but dairy products are rich in calcium and vitamin D. Epidemiological studies and interventional studies have shown similar trends between calcium / vitamin D intake and reduced chronic disease risk [11][12][13]. Calcium and vitamin D are critical to epithelial cell differentiation [23]. Differentiation, in turn, regulates growth (reducing outgrowth of premalignant lesions in organs such as the colon) and promotes barrier formation throughout the upper aerodigestive tract and digestive system (combating chronic inflammation).…”