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