Parathyroid hormone (PTH) is one of the two major hormones modulating calcium and phosphate homeostasis, the other being calcitriol (1,25-dihydroxyvitamin D) . The minute-to-minute regulation of serum ionized calcium is exclusively regulated through PTH, maintaining the concentration of this cation within a narrow range, through stimulation of renal tubular calcium reabsorption and bone resorption [2,3]. On a more chronic basis, PTH also stimulates the conversion of calcidiol (25-hydroxyvitamin D) to calcitriol in renal tubular cells, thereby stimulating intestinal calcium absorption.
PTH secretion is, in turn, regulated by serum ionized calcium acting via an exquisitely sensitive calcium-sensing receptor (CaSR) on the surface of parathyroid cells . The receptor has a long amino terminus, seven transmembrane segments, and a shorter intracellular carboxyl terminus (figure 1). When activated by a small increase in serum ionized calcium, the calcium-receptor complex acts via one or more guanine nucleotide-binding (G) proteins through second messengers such as intracellular calcium and inositol phosphates to inhibit PTH secretion and decrease renal tubular reabsorption of calcium. Conversely, the effect of deactivation of the receptor by a small decrease in serum ionized calcium is to stimulate PTH secretion.
NORMAL PTH SECRETION
PTH synthesis and degradation — Parathyroid hormone (PTH) is synthesized as a 115- amino acid polypeptide called pre-pro-PTH, which is cleaved within parathyroid cells at the N-terminal portion first to pro-PTH (90 amino acids) and then to PTH (84 amino acids). The latter is the major storage, secreted, and biologically active form of the hormone [5,6]. The biosynthetic process is estimated to take less than one hour. The N-terminal cleaved pre-sequence is rich in hydrophobic amino acids that are necessary for transport into the endoplasmic reticulum, while the basic pro-peptide directs accurate cleavage of pro-PTH into the mature 1-84 molecule . The C-terminal portion of PTH is also essential for the PTH secretory process . PTH 1-84 is secreted by exocytosis within seconds after induction of hypocalcemia . Calcium regulates not only the release but also the synthesis and degradation of PTH, in all its molecular forms as described below .
In addition to intact PTH, some inactive carboxyl-terminal fragments and small amounts of active amino-terminal fragments of PTH are present in the parathyroid glands. During hypocalcemia, intracellular degradation of PTH decreases, and mostly PTH 1-84 is secreted; in comparison, during hypercalcemia mostly biologically inactive carboxyl-terminal fragments of PTH are secreted [1,3,7]. These carboxy-terminal fragments include long, amino-terminally cleaved species, such as PTH 7-84, which possess several biological activities. (See "Parathyroid hormone assays and their clinical use", section on 'PTH fragments'.)
Under normocalcemic conditions, PTH 1-84 constitutes 20 percent of total circulating PTH molecules. This proportion increases to 33 percent under hypocalcemic conditions, and decreases to 4 percent in the presence of hypercalcemia . Once secreted, PTH is rapidly cleared from plasma through uptake principally by the liver and kidney, where PTH 1-84 is cleaved into amino- and carboxyl-terminal fragments that are then cleared by the kidney.