Novel Role of the Calcium-Sensing Receptor in Blood Pressure Modulation

Abstract

The calcium-sensing receptor (CaR) was cloned in 1993 from bovine parathyroid gland.1 Subsequently, the receptor was reported in a wide range of tissues and cell types. It belongs to the superfamily C of the G protein–coupled receptors, which are also known as 7 transmembrane receptors. The CaR is a promiscuous receptor that, in addition to extracellular calcium (Ca2+ o ), recognizes many other ligands.2 CaR ligands are divided into type I agonists, which are direct agonists, and type II, which act as allosteric modulators that change the affinity of the receptor to calcium and other cations. The newly developed calcimimetics are type II agonists that bind to the transmembrane domain and positively modulate the CaR.3 These drugs have been introduced recently in the treatment of uremic secondary hyperparathyroidism.4 The binding of Ca2+ o or other CaR agonists to the CaR elicits complex intracellular signals through modulation by the CaR of a wide array of intracellular signaling proteins, including G proteins and phospholipase C, which stimulates inositol triphosphate production. Downstream of or in parallel with phospholipase C, the CaR also activates mitogen-activated protein kinases (MAPKs). The most important physiological function of the CaR is to maintain and regulate systemic calcium homeostasis. In parathyroid glands, the CaR inhibits secretion of parathyroid hormone (PTH), the key calcium-regulating hormone. The CaR is also expressed in bone, kidney, and intestine, the major calcium-translocating organs. In the kidney, the receptor regulates renal sodium and ion transport, although the exact mechanisms of action are not fully established. In addition to organs involved in calcium homeostasis, the receptor is also widely expressed in other tissues, including blood vessels and cardiomyocytes. The CaR protein was first reported in perivascular nerves of isolated rat arteries and proposed to modulate vascular tone.5 Recently, the CaR …