The calcium-sensing receptor (CaSR) is a receptor found in the cell membrane of cells involved in regulating calcium (Ca++) levels. It detects small changes in the amount of Ca++ outside the cells. Ca++ binds to CaSR receptors in cells that secrete parathyroid hormone (PTH) and cells that produce calcitriol. When the receptor is activated by an increase in Ca++ levels in the blood, it inhibits PTH secretion and stimulates the production of calcitriol. Conversely, a decrease in blood Ca++ levels has the opposite effect on PTH and calcitriol secretion.

The CaSR also plays a role in maintaining calcium homeostasis by directly regulating the excretion of calcium by the kidneys. The CaSRs in a part of the kidney called the thick ascending limb (TAL) respond directly to changes in blood Ca++ levels and control calcium absorption. An increase in blood Ca++ levels activates the CaSR in the TAL, leading to a decrease in calcium absorption and an increase in urinary calcium excretion. On the other hand, a decrease in blood Ca++ levels causes an increase in calcium absorption by the TAL and a corresponding decrease in urinary calcium excretion. This direct effect of blood Ca++ levels on CaSRs in the TAL works together with changes in PTH, which regulates calcium reabsorption by another part of the kidney called the distal tubule, to regulate urinary calcium excretion and maintain calcium homeostasis.

Mutations in the gene responsible for CaSR can lead to disorders in calcium homeostasis. One such disorder is familial hypocalciuric hypercalcemia (FHH), which is caused by a mutation that inactivates the CaSR gene. In FHH, the regulation of PTH secretion by calcium is disrupted, resulting in elevated PTH levels at any level of blood Ca++ and failure of PTH to be suppressed in the presence of high blood calcium levels. Additionally, enhanced calcium reabsorption in the TAL and distal tubule occurs due to elevated PTH levels and impaired regulation of calcium transport by the CaSR in the kidneys. Another disorder, autosomal-dominant hypoparathyroidism, is caused by an activating mutation in the CaSR gene. Activation of CaSRs in this disorder causes abnormal regulation of PTH secretion, with decreased PTH levels at any level of blood Ca++. This leads to hypercalciuria (increased urinary calcium excretion), which is caused by the lower PTH levels and impaired regulation of calcium transport by the CaSR in the kidneys.

Phosphate (Pi) is an important component of various organic molecules, including DNA, RNA, ATP, nucleotides, nucleosides, phospholipids, and intermediates of metabolic pathways. Like calcium, it is a major component of bone. The concentration of Pi in the blood plays a crucial role in bone formation and resorption. It is also involved in maintaining acid-base balance as one of the many titratable acids in the urine. Approximately 85% of Pi is found in bone and teeth, 14% is located within cells, and 1% is present in the extracellular fluid. The normal concentration of Pi in the blood is around 3 to 4 mg/dL (1–1.5 mM). In the blood, Pi exists in ionized form (45%), as complexes (30%), and bound to proteins (25%). Deficiency of phosphate can lead to muscle weakness, rhabdomyolysis, and impaired bone mineralization, resulting in rickets in children and osteomalacia in adults.

An overview of phosphate homeostasis is depicted in the figure below.

[Figure 36.17: Overview of Pi homeostasis]
The calcium-sensing receptor (CaSR) is a receptor expressed in the plasma membrane of cells involved in regulating Ca++ homeostasis; it senses small changes in extracellular [Ca++]. Ca++ binds to CaSR receptors in PTH-secreting cells of the parathyroid gland and calcitriol-producing cells of the proximal tubule. Activation of the receptor by an increase in plasma [Ca++] results in inhibition of PTH secretion and production of calcitriol by the proximal tubule. Moreover, reduction in PTH secretion also contributes to decreased production of calcitriol because PTH is a potent stimulus of calcitriol synthesis. By contrast, a fall in plasma [Ca++] has the opposite effect on PTH and calcitriol secretion.
The CaSR also maintains Ca++ homeostasis by directly regulating Ca++ excretion by the kidneys. CaSRs in the TAL respond directly to changes in plasma [Ca++] and regulate Ca++ absorption. An increase in plasma [Ca++] activates CaSR in the TAL and inhibits Ca++ absorption, thereby stimulating urinary Ca++ excretion. By contrast, a fall in plasma [Ca++] leads to an increase in Ca++ absorption by the TAL and a corresponding decrease in urinary Ca++ excretion. Thus the direct effect of plasma [Ca++] on CaSRs in the TAL acts in concert with changes in PTH, which regulates Ca++ reabsorption by the distal tubule to regulate urinary Ca++ excretion and thereby maintain Ca++ homeostasis.
Mutations in the gene coding for CaSR cause disorders in Ca++ homeostasis. Familial hypocalciuric hypercalcemia (FHH) is a haploinsufficient state caused by an inactivating mutation of CaSR. The hypercalcemia is caused by deranged Ca++-regulated PTH secretion (i.e., the set point for Ca++-regulated PTH secretion is shifted such that PTH levels are elevated at any level of plasma [Ca++], and are not suppressed in the setting of hypercalcemia). The hypocalciuria is caused by enhanced Ca++ reabsorption in the TAL and distal tubule owing to elevated PTH levels and defective CaSR regulation of Ca++ transport in the kidneys. Autosomal-dominant hypoparathyroidism is caused by an activating mutation in CaSR. Activation of CaSRs causes deranged Ca++-regulated PTH secretion (i.e., the set point for Ca++-regulated PTH secretion is shifted such that PTH levels are decreased at any level of plasma [Ca++]). Hypercalciuria results and is caused by decreased PTH levels and defective CaSR-regulated Ca++ transport in the kidneys.
Pi is an important component of many organic molecules, including DNA, RNA, ATP, nucleotides, nucleosides, and phospholipids and intermediates of metabolic pathways. Like Ca++ it is a major constituent of bone. Its concentration in plasma is an important determinant of bone formation and resorption. In addition, urinary Pi is an important buffer (i.e., it is one of many titratable acids) involved in the maintenance of acid-base balance (see ). Some 85% of Pi is located in bone and teeth, 14% is located in the ICF, and 1% is located in the ECF. Normal plasma • Fig. 36.17 Overview of Pi homeostasis. (From Koeppen BM, Stanton BA. Renal Physiology. 5th ed. Philadelphia: Elsevier; 2013.) [Pi] is 3 to 4 mg/dL (1–1.5 mM). Pi in plasma is ionized (45%), complexed (30%), and bound to protein (25%). Phosphate deficiency causes muscle weakness, rhabdomyolysis, and reduced bone mineralization resulting in rickets (in children) and osteomalacia (in adults).
Overview of Phosphate Homeostasis
A general scheme of Pi homeostasis is shown in