The complexation of Ca++ occurs with various anions in plasma, such as HCO3−, citrate, and SO42−, while Pi is complexed with various cations, including Na+ and K+. Parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D are the primary hormones responsible for regulating normal blood levels of Ca and Pi in humans, and are referred to as calciotropic hormones. The structure, synthesis, and secretion of PTH and 1,25-dihydroxyvitamin D, as well as their receptors, will be discussed initially. Subsequently, the actions of PTH and 1,25-dihydroxyvitamin D on the gut, bone, and kidney, which are the key sites of Ca/Pi homeostasis, will be addressed. The principal cell type in the parathyroid gland is the chief cell, which is primarily targeted by PTH to protect against hypocalcemia. PTH also stimulates the production of 1,25-dihydroxyvitamin D through a positive feed-forward loop. PTH is secreted as an 84-amino acid polypeptide and undergoes proteolytic processing to become pro-PTH in the endoplasmic reticulum, and then PTH in the Golgi and secretory vesicles. The PTH receptor, also known as the PTH/PTHrP receptor, is expressed on osteoblasts in bone and in the proximal and distal tubules of the kidney, mediating the systemic actions of PTH. Additionally, the PTH/PTHrP receptor is expressed in developing organs where PTHrP has paracrine functions. Vitamin D, which is converted to its active form, 1,25-dihydroxyvitamin D or calcitriol, through two hydroxylation reactions, plays a critical role in calcium absorption. The parathyroid chief cell senses extracellular Ca++ levels through the plasma membrane calcium-sensing receptor (CaSR), and a decrease in circulating Ca++ stimulates PTH secretion.
Ca++ isbound(i.e.,complexed)tovariousanionsinplasma,includingHCO3− ,citrate,andSO42− .Piiscomplexedtovariouscations,includingNa+ andK+ .FromKoeppenBM,StantonBA.Renal Physiology. 4thed.Philadelphia:Mosby;2007.
Physiological Regulation of Calcium and Phosphate: Parathyroid Hormone and 1,25-Dihydroxyvitamin D C
PTH and 1,25-dihydroxyvitamin D are the two physiologically most important hormones dedicated to mainte- nance of normal blood Ca and Pi in humans. As such they are referred to as calciotropic hormones. The structure, synthesis, and secretion of these two hormones and their receptors will be discussed first. In the following section, the detailed actions of PTH and 1,25-dihydroxyvitamin D on the three key sites of Ca/Pi homeostasis (i.e., gut, bone, and kidney) are discussed.
The predominant parenchymal cell type in the parathyroid B gland is the principal (also called chief) cell (
Fig. 40.2
PTH is the primary hormone that protects against hypocalcemia. The primary targets of PTH are bone and the kidneys. PTH also functions in a positive feed-forward loop by stimulating production of 1,25-dihydroxyvitamin D.
•Fig. 40.2 AandB,Histologyofparathyroidglands.A,adiposetissuewithinparathyroidglands;C,capillaries;O,oxyphilcells;P,principalorchiefcells.(FromYoungBetal.Wheater’s Functional Histology. 5thed.Philadelphia:ChurchillLivingstone;2006.)
Structure, Synthesis, and Secretion
PTH is secreted as an 84–amino acid polypeptide and is synthesized as a prepro-PTH, which is proteolytically processed to pro-PTH in the endoplasmic reticulum and then to PTH in the Golgi and secretory vesicles. PTH has a short half-life in the circulation (2 minutes), consistent with its role in minute-to-minute regulation of plasma calcium.
Because the PTH receptor also binds PTH-related peptide (PTHrP), it is usually referred to as the PTH/PTHrP receptor. The PTH/PTHrP receptor is expressed on osteoblasts in bone and in the proximal and distal tubules of the kidney, and it is the receptor that mediates the systemic actions of PTH. However, the PTH/PTHrP receptor is also expressed in many developing organs in which PTHrP has important paracrine functions. One such example is regulation of chondrocyte proliferation in the growth plate during endochondral bone growth.
Vitamin D is a prohormone that must undergo two successive hydroxylation reactions to become the active form known as 1,25-dihydroxyvitamin D or calcitriol (
Fig.
40.5 ). This hormone plays a critical role in Ca absorption
Extracellular[Ca++]issensedbytheparathyroidchiefcellthroughaplasmamembranecalcium-sensing receptor (CaSR). TheprimarysignalthatstimulatesPTHsecretionisadecreaseincirculating[Ca++](