Chemistry

Human PTH consists of a single polypeptide chain of 84 amino acids (molecular weight ~9500). Biological activity is associated with the N-terminal portion and residues 1-27 are required for optimal binding and activation of the PTH receptor. PTH (1-84) has a t122 in plasma of 2—5 minutes and is predominantly (~90%) cleared by the liver and kidney.

physiological functions The primary function of PTH is to maintain a constant concentration of Ca2+ in the extracellular fluid. The principal processes regulated are renal Ca2+ reabsorption and mobilization of bone Ca2+ (Figure 61-3). The actions of PTH on tissues are mediated by at least two GPCRs that couple to Gs and Gq in cell-specific manners.

figure 61-3 Calcium homeostasis and its regulation by parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D.

PTH has stimulatory effects on bone and kidney, including the stimulation of 1a-hydroxylase activity in kidney mitochondria leading to the increased production of the biologically active hormone 1,25-dihydroxyvitamin D (calcitriol) from 25-hydroxyvitamin D (see Figure 61-5). Solid lines indicate a positive effect; dashed lines refer to negative feedback.

absorption absorption figure 61-3 Calcium homeostasis and its regulation by parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D.

PTH has stimulatory effects on bone and kidney, including the stimulation of 1a-hydroxylase activity in kidney mitochondria leading to the increased production of the biologically active hormone 1,25-dihydroxyvitamin D (calcitriol) from 25-hydroxyvitamin D (see Figure 61-5). Solid lines indicate a positive effect; dashed lines refer to negative feedback.

Regulation of Secretion Plasma Ca2+ is the major regulator of PTH secretion; hypocalcemia stimulates and hypercalcemia inhibits PTH secretion. Sustained hypocalcemia also induces parathyroid hypertrophy and hyperplasia. Changes in Ca2+ modulate PTH secretion by parathyroid cells via the calcium-sensing receptor (CaSR), a GPCR that couples with Gq-PLC and Gi. Occupancy of the CaSR by Ca2+inhibits PTH secretion; thus, the extracellular concentration of Ca2+is controlled by an endocrine negative-feedback system, the afferent limb of which senses the ambient activity of Ca2+ and the efferent limb of which releases PTH that then acts to increase Ca2+. The active vitamin D metabolite calcitriol directly suppresses PTH gene expression.

Effects on Bone PTH increases bone resorption and thereby increases Ca2+ delivery to the extracellular fluid. The apparent cellular target for PTH is the osteoblast. PTH also recruits osteo-clast precursors to form new bone remodeling units (see below).

Effects on Kidney In the kidney, PTH enhances the efficiency of Ca2+ reabsorption, inhibits tubular reabsorption of phosphate, and stimulates conversion of 25-OHD to calcitriol (Figure 61-3, see below). As a result, filtered Ca2+ is avidly retained and its plasma concentration increases, whereas phosphate is excreted and its plasma concentration falls. Newly synthesized calcitriol interacts with specific high-affinity vitamin D receptors (VDRs) in the intestine to increase the efficiency of calcium absorption, thereby also increasing the plasma Ca2+ concentration.

PTH increases tubular reabsorption of Ca2+, primarily in the distal nephron, with concomitant decreases in urinary Ca2+ excretion. Many of these effects are mediated by G-induced increases in intracellular cyclic AMP, and subsequent stimulation of the epithelial Ca2+ channel TRPV5. As the plasma Ca2+ concentration increases, the filtered load of Ca2+ also increases; the tubular capacity to reabsorb Ca2+ is exceeded and hypercalciuria results. Conversely, reduction of serum PTH depresses tubular reabsorption of Ca2+ and thereby increases urinary Ca2+ excretion. When the plasma Ca2+ concentration falls below 7 mg/dL, the filtered load of Ca2+ declines to the point that Ca2+ is almost completely reabsorbed despite reduced tubular capacity.

PTH increases renal excretion of P. by decreasing its reabsorption, an effect mediated by retrieval of the Na-P. cotransporter from the luminal membrane rather than a decrease in the number of cotransporters. Fibroblast growth factor 23 also plays important roles in regulating phosphate reabsorption.

The final step in the activation of vitamin D to calcitriol occurs in the kidney proximal tubular cells. The key enzyme in this process, 1a-hydroxylase, is a mitochondrial CYP that is regulated by PTH, P, and Ca2+ (see below).

INTEGRATED REGULATION OF EXTRACELLULAR Ca2+ CONCENTRATION

BY PTH Even modest reductions of serum Ca2+ stimulate PTH secretion. Acutely, the regulation of tubular Ca2+ reabsorption by PTH suffices to maintain plasma Ca2+ homeostasis. With more prolonged hypocalcemia, renal 1a-hydroxylase is stimulated; this enhances the synthesis and release of calcitriol, which directly stimulates intestinal calcium absorption (Figure 61-3). Finally, PTH and the resulting increase in calcitriol also stimulate Ca2+ release from bone.

When plasma Ca2+ rises, PTH secretion is suppressed and tubular Ca2+ reabsorption decreases. The reduced PTH promotes renal phosphate conservation, and both the decreased PTH and the increased phosphate reduce calcitriol production and thereby decrease intestinal Ca2+ absorption. Finally, bone remodeling is suppressed. These physiological events provide an integrated response to positive or negative excursions of plasma Ca2+ concentration.

Vitamin D

Vitamin D traditionally was viewed as a permissive factor in calcium metabolism, facilitating efficient absorption of dietary calcium and allowing full expression of PTH action. Vitamin D is a hormone, rather than a vitamin, and plays an active role in calcium homeostasis.

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