The most potent of the cations modulating PTH release and the secretagogue that is most important in altering PTH release under physiologic and pathophysiologic circumstances is the calcium ion (Fig. 51-3). Although there is an inverse relationship between ambient calcium levels and PTH release, this is a curvilinear rather than proportional relationship.43 From in vivo studies of cattle, maximal rates of PTH secretion of ˜16 ng/kg per minute appear to be rapidly achieved at calcium levels below 7.5–8.0 mg/dL (1.88–2.00 mmol/L). When calcium levels are reduced from 10.0 to 9.5 mg/dL (2.50–2.38 mmol/L), a small and gradual increase in PTH secretion occurs that does exhibit a proportional relationship to the ambient calcium level. Half-maximal secretion rates normally occur at calcium levels of ˜8.5 mg/dL (2.12 mmol/L), which is the set-point for PTH secretion. Basal secretion rates result after ambient calcium levels have risen above 11 mg/dL
(2.75 mmol/L) and appear to persist despite further increases in calcium concentration, even up to 16–18 mg/dL (4.00–4.50 mmol/L). Similar results have been observed in studies with human parathyroid tissue in vitro. The nonsuppressible (more correctly, non–calcium suppressible) component of constitutive PTH secretion appears to comprise mainly bioinactive midregion and COOH-terminal fragments. However, direct determination of the activity of hormonal material released when calcium levels are markedly elevated also demonstrates some bioactivity.

This inverse relationship between PTH and extracellular calcium contrasts with the influence of the calcium ion as a secre-tagogue in most other secretory systems in which elevations in this ion enhance release of the secretory product. This distinction between the parathyroid cell and other secretory cells is maintained intracellularly, where elevations rather than decreases in cytosol calcium correlate with decreased PTH release.44 Alterations in extracellular fluid calcium levels are transmitted through a parathyroid plasma membrane calcium sensing receptor that couples through a G-protein complex to phospholipase C. Increases in extracellular calcium lead to increases in inositol 1,4,5-trisphosphate (IP₃) and mobilization of intracellular calcium stores. The manner in which this inhibits hormone secretion is not understood. Although it would be anticipated that increases in diacylglycerol would accompany IP₃ increases caused by hydrolysis of phosphoinositides, activate protein kinase C, and result in reduced PTH secretion, this does not appear to occur in the parathyroid cell.45 Paradoxically, agents that do stimulate protein kinase C, such as phorbol esters, stimulate rather than inhibit hormone secretion. This may be a result of phosphorylation of amino acids in the COOH-terminus of the CaSR, leading to its desensitization by blocking interaction of the receptor with its G protein. The precise steps in the pathway from changes in extracellular calcium levels to hormone release remain to be elucidated.

The parathyroid cell Ca²⁺-sensing receptor cDNA was identified by expression cloning in Xenopus laevis oocytes.46 The mRNA of the human receptor encodes a polypeptide of 1078 amino acids that is predicted to contain a very large extracellular domain of ˜600 amino acids and a seven transmembrane-spanning region characteristic of G-protein–coupled cell-surface receptors. Compared with the other known G-protein–coupled receptor family members, the Ca²⁺-sensing receptor shows some homology with the metabotropic glutamate, γ-aminobutyric acid-B, and vomeronasal odorant receptors, sharing conserved cysteine residues and a hydrophobic sequence in the NH₂-terminal region. The Ca²⁺-sensing receptor has a low affinity for Ca²⁺, and consistent with this, the receptor sequence does not contain any of the Ca²⁺ binding motifs found in high-affinity calcium-binding proteins. Highly acidic regions in the extracellular NH₂-terminal domain and the second extracellular loop may bind calcium as they do in other known low-affinity Ca²⁺ binding proteins. Besides the parathyroid, the Ca²⁺-sensing receptor is also expressed in other cells having Ca²⁺-sensing functions, such as those of the kidney tubule, the calcitonin-secreting thyroid C-cells; and in diverse other organs and tissues such as brain, keratinocytes, gastrointestinal tract, and retina. Neomycin binds the receptor, possibly accounting for the toxic renal effects of aminoglycoside antibiotics.

The human Ca²⁺-sensing receptor gene has been partially characterized and shown to consist of seven exons spanning more than 20 kb of genomic DNA.47 The long extracellular domain is encoded by the first two to six exons, and the remainder of the molecule is encoded by exon seven. Exons 1A and 1B encode two alternative 5′ untranslated regions of the CaSR mRNA. Inherited abnormalities of the CaSR gene, located on chromosome 3p13.3-21, can lead either to hypercalcemia or to hypocalcemia depending on whether they are inactivating or activating, respectively. Heterozygous loss-of-function mutations give rise to familial (benign) hypocalciuric hypercalcemia (FHH), in which the lifelong hypercalcemia is asymptomatic.47,48 and 49 The homozygous condition manifests itself as neonatal severe hyperparathyroidism (NSHPT), which is a rare disorder characterized by extreme hypercalcemia and the bony changes of hyperparathyroidism that occur in infancy.50,51 In several cases of NSHPT the parents are normocalcemic, and the cases seem to be sporadic. Autosomal-dominant hypocalcemia (ADH) is caused by gain-of-function mutations in the CaSR gene.52 Autosomal-dominant hypocalcemia may be asymptomatic or present with neonatal or childhood seizures. Because of the overactive CaSR in the nephron, these patients are at greater risk of developing renal complications during vitamin D therapy than are patients with idiopathic hypoparathyroidism. A common polymorphism in the intracellular tail of the CaSR, Ala to Ser at position 986, has a modest effect on the serum calcium concentration in healthy individuals.53 CaSR polymorphisms might also affect urinary calcium excretion and bone mass; therefore, the CaSR is a candidate gene for involvement in disorders such as idiopathic hypercalciuria and osteoporosis.