HORMONAL CONTROL OF CALCIUM HOMEOSTASIS

Part of “CHAPTER 49 – PHYSIOLOGY OF CALCIUM METABOLISM“

A complex homeostatic system has evolved that is designed to maintain near constancy of Ca²⁺_o through calciotropic hormone, and direct, Ca²⁺_o-induced alterations in the GI, renal, and/or skeletal handling of Ca²⁺ (Fig. 49-2).4,5,6 and 7 Usually, this is accomplished in such a way that extracellular (including skeletal) and cellular Ca²⁺ homeostasis and balance are maintained simultaneously. Conditions of gross Ca²⁺ excess, however, may induce positive Ca²⁺ balance (e.g., deposition of Ca²⁺ in bone and soft tissues) to maintain a normal or near-normal level of Ca²⁺_o.Conversely, severe Ca²⁺ deficiency leads to mobilization of skeletal Ca²⁺ to preserve normocalcemia. Overall Ca²⁺_o homeostasismay be understood in terms of the following general principles: (a) The first priority of the homeostatic system is to maintain a normal level of Ca²⁺_o; (b) with moderate stresses on the system, intestinal and renal adaptations are usually sufficient to sus- tain Ca²⁺_o homeostasis without changes in net bone mass; and (c) with severe hypocalcemic stresses, skeletal stores of Ca²⁺ are mobilized to maintain Ca²⁺_o homeostasis, potentially compromising the structural integrity of the skeleton.

FIGURE 49-2. The hormonal control of calcium and phosphate homeostasis by parathyroid hormone (PTH) and vitamin D (solid lines and arrows). Ca²⁺ regulates PTH secretion in an inverse fashion. In turn, PTH affects renal handling of calcium and phosphate as well as renal synthesis of 1,25(OH)₂D₃. PTH and 1,25(OH)₂D₃ synergistically mobilize calcium and phosphate from bone, whereas the latter increases intestinal absorption of both ions. Also shown are direct actions of calcium and phosphate ions on tissues involved in maintaining mineral ion homeostasis (lines and arrows), illustrating the role of these ions as extracellular, first messengers. For example, elevated Ca²⁺_o directly suppresses renal synthesis of 1,25(OH)₂D₃, tubular reabsorption of Ca²⁺ in the thick ascending limb, and the resorptive activities of osteoclasts. Thus, calcium ions modulate their own homeostasis not only through direct actions on the secretion of calciotropic hormones but also by exerting direct effects on target tissues that tend to lower Ca²⁺_o. In effect, calcium and phosphate ions act as Ca²⁺_o-regulating factors or “hormones” because they transmit information about the state of mineral ion metabolism from one part of the homeostatic system to other parts. For additional details, see text. (Reproduced from Brown EM, Pollak M, Hebert SC. Cloning and characterization of extracellular Ca²⁺-sensing receptors from parathyroid and kidney. Molecular physiology and pathophysiology of Ca²⁺-sensing. The Endocrinologist 1994; 4:419.)

The homeostatic system comprises two essential components. The first is several cell types that sense changes in Ca²⁺_o and respond with appropriate alterations in their output of Ca²⁺_o-regulating hormones (PTH, calcitonin, and 1,25[OH]₂D₃). The parathyroid glands are key sensors of variations in Ca²⁺_o, responding withalterations in PTH secretion that are inversely related to ambient levels of Ca²⁺_o.7 Parathyroid cells recognize changes in Ca²⁺_o through a cell-surface Ca²⁺_o-sensing receptor14—described in more detail later—that is a member of the superfamily of G protein– coupled receptors that includes the receptors for PTH and calcitonin. The C cells of the thyroid gland also respond to changes in Ca²⁺_o with alterations in calcitonin secretion—with high Ca²⁺_o stimulating calcitonin secretion—through the same Ca²⁺_o-sensing receptor. The physiologic relevance of changes in circulating levels of calcitonin in adult humans, however, remains uncertain (see Chap. 53). Finally, the production of 1,25(OH)₂D₃ is likewisedirectly regulated by Ca²⁺_o, with hypocalcemia stimulating its synthesis in the renal proximal tubule and hypercalcemia inhibiting it.15 The second key component of the homeostatic system is the effector cells that control the renal, intestinal, and skeletal handling of Ca²⁺. The translocation of calcium and phosphate ions into or out of the extracellular fluid by these tissues is regulated by PTH, calcitonin, and 1,25(OH)₂D₃ as well as by mineral ions themselves.

The overall operation of the homeostatic system is as follows (see Fig. 49-2). In response to slight decrements in the Ca²⁺_o, forexample, a prompt increase occurs in the secretory rate for PTH. This hormone has several important effects on the kidney, which include inducing phosphaturia, enhancing distal tubular reabsorption of Ca²⁺, and increasing generation of 1,25(OH)₂D₃ from 25-hydroxyvitamin D₃, or 25(OH)D₃.16 The increased circulating levels of this potent metabolite of vitamin D₃ directly stimulate absorption of calcium and phosphate by the intestine through independent transport systems.4,5 and 6,17 PTH and 1,25(OH)₂D₃ also synergistically enhance the net release of calcium and phosphate from bone. The increased movement of Ca²⁺ into the extracellular fluid from intestine and bone, coupled with PTH-induced renal retention of this ion, normalize circulating levels of Ca²⁺_o, thereby inhibiting PTH release and closing the negative-feedback loop. In addition, 1,25(OH)₂D₃, formed in response to the action of PTH on the kidney, directly inhibits the synthesis and secretion of PTH,7 contributing to the negative feedback control of parathyroid function by the homeostatic system. Excess phosphate
mobilized from bone and intestine is excreted in the urine via the phosphaturic action of PTH.

Both calcium and phosphate ions can exert direct effects on various cells and tissues involved in mineral ion metabolism (see Fig. 49-2). For instance, calcium ions not only reduce PTH secretion but also directly inhibit proximal tubular synthesis of15 stimulate the function of osteoblasts,18 and inhibit 1,25(OH)₂D₃, the function of osteoclasts.19 Phosphate ions reduce 1α-hydroxylation of vitamin D, stimulate bone formation, inhibit bone resorption,4,5,6 and 7 and stimulate various aspects of parathyroid function,20 as described in more detail in the next section. These actions play important roles in mineral ion homeostasis by enabling both the hormone-secreting and effector elements of the homeostatic system to sense changes in the ambient concentrations of mineral ions and to respond in a physiologically appropriate manner. Indeed, by virtue of their direct actions on cells involved in mineral ion metabolism, calcium and phosphate ions can be viewed as serving a hormone-like role as extracellular first messengers.7 Although the cloning of the Ca²⁺_o-sensing receptorthat mediates direct actions of Ca²⁺_o on parathyroid and renalfunction has clarified substantially how cells sense Ca²⁺_o,21 the mechanism underlying phosphate sensing remains obscure.

REGULATION OF PARATHYROID HORMONE SECRETION BY CALCIUM AND OTHER FACTORS

A steep, inverse sigmoidal relationship exists between PTH secretion and Ca²⁺_o (Fig. 49-3)—hence, the exquisite sensitivity ofthe parathyroid gland to Ca²⁺_o that is critical to maintaining stable normocalcemia.7 This sigmoidal function can be described in terms of maximal and minimal secretory rates, midpoint or set-point, and slope at the midpoint (see Fig. 49-3). The maximal secretory rate provides a measure of the acute secretory reserve of the gland in response to a maximal hypocalcemic stress. Maximal secretory capacity increases with parathyroid cellular hyper-plasia, as in primary or secondary hyperparathyroidism.4,5,6 and 7,21 The secretion of PTH from the parathyroid cell apparently is incapable of being totally suppressed, even at very high levels of Ca²⁺_o(see Fig. 49-3). Importantly, this implies that a sufficient mass of even normal parathyroid tissue could cause hypersecretion of PTH with resultant hypercalcemia. This has, in fact, been documented in rats by transplanting sufficient numbers of normal rat parathyroid glands to cause hypercalcemia in the recipient animals.22 This may, in part, contribute to the hypersecretion of PTH in hypercalcemic hyperparathyroidism The setpoint of normal human parathyroid cells in vitro is ˜1.0 mmol/L of ionized Ca²⁺and is close to the ambient level of Ca²⁺_o in humans (1.1–1.3mmol/L).7 This parameter is important in determining the level at which the Ca²⁺_o is set by the homeostatic system (the setpointfor Ca²⁺_o is slightly higher than that for the parathyroid cell per se, also being a function of the tissues that are targets for the actions of PTH). In primary hyperparathyroidism, the setpoint of pathologic parathyroid cells is increased to 1.2 to 1.4 mmol/L Ca²⁺, or sometimes higher, and the serum Ca²⁺ concentration is correspondingly reset to an elevated level7,21 (see Chap. 58). The steep slope of the relationship between PTH release and Ca²⁺_oensures a large change in secretory rate for a small change in Ca²⁺_o and is important in maintaining the serum Ca²⁺ concentra- tion within a narrow range. In addition to its sensitivity to Ca²⁺_o,the parathyroid cell alters its secretory rate within seconds to a perturbation in Ca²⁺_o and may also be responsive to other variables, such as the rate and direction of the change.23,24

FIGURE 49-3. A, Relationship between parathyroid hormone (PTH) secretion and extracellular Ca²⁺ concentration in normal human parathyroid cells. Dispersed parathyroid cells were prepared and incubated with the indicated ionized Ca²⁺ concentrations. The PTH released was determined using a radioimmunoassay that recognizes the intact hormone and the COOH-terminal fragments of the molecule. B, The four parameters that can be used to describe the relationship between PTH secretion and the extracellular ionized Ca²⁺ concentration: maximal and minimal secretory rates at low and high Ca²⁺ concentrations, respectively; slope of the curve at its midpoint; and setpoint (the level of Ca²⁺ producing half of the maximal inhibition of PTH release). (A from Brown EM. Regulation of the synthesis, metabolism and actions of parathyroid hormones. In: Brenner BM, Stein H, eds. Contemporary issues in nephrology, vol 2. Divalent ion homeostasis. New York: Churchill-Livingstone, 1983.)

The technique of expression cloning in Xenopus laevis oocytes enabled isolation of a phosphoinositide-coupled, Ca²⁺_o-sensing receptor from bovine parathyroid gland through which parathyroid, kidney, and other cells sense Ca²⁺_o.14 This receptor has a large amino-terminal extracellular domain that is involved in binding Ca²⁺_o, followed by seven membrane-spanning segments characteristic of the superfamily of G protein–coupled receptors, and a cytoplasmic carboxy terminus (Fig. 49-4). In addition to recognizing Ca²⁺_o, the receptor responds to other polyvalent cations as well, including Mg²⁺, trivalent cations, and neomycin.14 The possibility exists, therefore, that the Ca²⁺_o-sensing receptor can function as a Mg²⁺_o-sensing receptor, and that some of the directeffects of Ca²⁺_o as well as the toxic actions of aminoglycosides on the kidney are mediated through it.21 The receptor plays a key role in Ca²⁺_o sensing by the parathyroid and kidney because the human homolog of the receptor harbors inactivating or activating mutations in several human genetic diseases that manifest abnormal Ca²⁺_o sensing.21 In familial hypocalciuric hypercalcemia (FHH),25 individuals with heterozygous inactivating mutations of the Ca²⁺_o-sensing receptor have mild to moderate hypercalcemia with inappropriately normal (e.g., nonsuppressed) circulating levels of PTH and normal or even frankly low levels of urinary calcium excretion. In contrast, persons with homozygous FHH, which presents clinically as neonatal severe hyperparathyroidism (NSHPT), have severe hypercalcemia with marked hyperparathyroidism.25 (NSHPT can also be caused by compound heterozygous inactivating mutations of the Ca²⁺_o-sensing receptor [i.e.,
patients harbor a different mutation in each allele of the receptor26] or by the presence of heterozygous inactivating mutations that exert a dominant negative effect on the wild-type receptor.27) Finally, some families with an autosomal dominant or, occasionally, a sporadic form of hypocalcemia accompanied by relative hypercalciuria (e.g., inappropriately high for the serum calcium concentration) harbor activating mutations in this receptor, a finding that provides further evidence of its importance in Ca²⁺_o sensing in the parathyroid and kidney.28

FIGURE 49-4. Proposed structural model of the predicted bovine parathyroid Ca²⁺-sensing receptor protein. The large amino-terminal domain is located extracellularly and contains nine consensus N-glycosylation sites that are shown as branched chains. Amino acids of the deduced protein are shown at intervals of 50 in the amino-terminal domain. The amino-acid segments that comprise each of the seven predicted membrane-spanning helices are numbered (M1–M7). Potential protein kinase C (PKC) phosphorylation sites are also shown. Each symbol (circle or triangle) represents an individual amino acid; those that are conserved with the metabotropic glutamate receptors are shown as solid symbols, of which acidic residues are indicated by solid triangles and all others by solid circles. Also indicated are multiple cysteine residues conserved with the metabotropic glutamate receptors (which may be involved in stabilizing the large extracellular domain) as well as clusters of acidic residues in the extracellular domain (open and solid triangles) that could be involved in binding of Ca²⁺ and other polyvalent cations. (SP, signal peptide; HS, hydrophobic segment.) (From Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca²⁺-sensing receptor from bovine parathyroid. Nature 1993; 366:575.)

In addition to being present in parathyroid, the Ca²⁺_o-sensing receptor is also present along most of the renal tubule29; it is present at the highest levels in the cortical thick ascending limb of the nephron (a segment that is likely responsible for the abnormal renal handling of Ca²⁺ in FHH).25 Receptor transcripts are also found in thyroid, brain, and several other tissues, including intestine and bone, as described later.30 The presence of the receptor in kidney probably accounts for several of the long-recognized but poorly understood direct effects of Ca²⁺_o on renal function (such as the reduced urinary concentrating ability encountered in some hypercalcemic patients).31 In the thyroid, the Ca²⁺_o-sensing receptor resides almost exclusively in the C cells and is thought to mediate the stimulatory effect of elevated Ca²⁺_o on calcitonin secretion. Ca²⁺_o-sensing receptors in the brain might mediate as yet unknown actions of Ca²⁺_o on neuronal function.30 Interestingly, among the G protein–coupled receptors, the Ca²⁺_o-sensing receptor exhibits only limited homology with three subclasses of receptors sharing its overall topology, particularly the presence of a very large amino-terminal extracellular domain. These are the metabotropic glutamate receptors (mGluRs), targets for glutamate, the major excitatory neurotransmitter in the brain; the GABA_B receptor, which is activated by γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain; and a family of putative pheromone receptors.30 All three classes of receptor presumably arose from a common ancestral gene. Further understanding of their structural similarities may clarify previously unknown relationships between Ca²⁺_o homeostasis or other functions of Ca²⁺ in the nervous system and in systemic Ca²⁺_o homeostasis.

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