The Calcium-Sensing Receptor and the Parathyroid: Past, Present, Future

Abstract

Parathyroid hormone (PTH) defends the extracellular fluid from hypocalcemia and has powerful and well-documented actions on the skeleton and renal tubular system. To achieve a satisfactory stable plasma calcium level, the secretion of PTH, and the resulting serum PTH level, is titrated carefully to the prevailing plasma ionized Ca²⁺ concentration via a Ca²⁺ sensing mechanism that mediates feedback inhibition of PTH secretion. Herein, I consider the properties of the parathyroid Ca²⁺ sensing mechanism, the identity of the Ca²⁺ sensor, the intracellular biochemical mechanisms that it controls, the manner of its integration with other components of the PTH secretion control mechanism, and its modulation by other nutrients. Together the well-established, recently elucidated, and yet-to-be discovered elements of the story constitute the past, present, and future of the parathyroid and its calcium-sensing receptor (CaSR).

Keywords: Calcimimetics; adenylate cyclase; calcilytics; calcium-sensing receptor; heterotrimeric G proteins; mineral metabolism; parathyroid; phospholipase C.

Figure 1

The calciostat in parathyroid cells. Left: A representation of the feedback mechanism by which PTH elevates the serum^* Ca²⁺ concentration and Ca²⁺ feeds back on the parathyroid to suppress PTH secretion in a process mediated by the CaSR. Right: Human parathyroid cells were perifused with HEPES-buffered physiological saline solutions containing various Ca²⁺ concentrations and samples of perifusate were collected at various times and subsequently analyzed for PTH1–84 as described in Conigrave et al. (2004). The results have been re-drawn. ^*Total and ionized calcium concentrations are comparable in serum and plasma since the major calcium-binding protein, albumin is present in similar concentrations in both these fluids.

Figure 2

Stimulated and spontaneous mechanisms in support of PTH secretion and its inhibition by high Ca²⁺_o. PTH secretion and its inhibition by high Ca²⁺_o arises from two distinct mechanisms. One mechanism is supported by exogenous agonists, including neurotransmitters or hormones, that activate G_s-coupled GPCRs as shown in (A) (left and right). PTH secretion continues provided Ca²⁺_o remains low but is promptly inhibited by G_i-dependent inhibition of adenylate cyclase in the presence of high Ca²⁺_o. The mechanism by which the Ca²⁺_o sensor, now known to be the CaSR, preferentially binds to G_i in this context is not known but might depend on local protein kinase-A (PK-A) activation. A second mechanism occurs spontaneously and may be supported by constitutive G_s-coupled GPCR activity (as shown in B; left and right) or by autocrine/paracrine production of receptor activators. PTH secretion via this second mechanism continues provided Ca²⁺_o remains low but is inhibited by high Ca²⁺_o-induced G_q/11-dependent activation of intracellular Ca²⁺ mobilization or Ca²⁺ influx (not shown). One possible mechanism by which increased intracellular free Ca²⁺ concentration (Ca²⁺_i) suppresses PTH secretion is shown via Ca²⁺_i-dependent inhibition of adenylate cyclase. ^*Receptor activated in the absence of neuronal or hormonal stimuli.