Parathyroid Hormone Synthesis and Regulation

Parathyroid hormone (PTH) is the principal hormone that defends the extracellular calcium concentration. It is an 84-amino-acid peptide synthesized and secreted by the chief cells of the four parathyroid glands. Its synthesis, storage, and especially its rapid secretion are tightly governed by extracellular calcium, sensed through the calcium-sensing receptor, so that even small falls in serum calcium prompt an immediate rise in PTH release.

Definition

Parathyroid hormone is an 84-amino-acid peptide secreted by parathyroid chief cells whose release is inversely regulated by extracellular ionized calcium through the calcium-sensing receptor, and which acts to raise serum calcium.

Scope

This topic covers how PTH is made and how its secretion is controlled: the precursor processing from preproPTH to the mature 84-residue peptide, the role of the calcium-sensing receptor in setting the inverse relationship between serum calcium and PTH, and the modulation of the gland by vitamin D and phosphate. The downstream actions of PTH on kidney and bone are treated in a companion topic. This is a reference-educational account of normal physiology, not clinical guidance.

Key concepts

• Chief cells of the parathyroid gland
• PreproPTH and proPTH processing
• Mature PTH(1-84)
• Calcium-sensing receptor (CaSR)
• Inverse sigmoidal calcium-PTH relationship
• Set point for calcium
• Suppression of PTH by calcitriol and hypophosphatemia
• Carboxyl-terminal PTH fragments

Mechanisms

PTH is translated as preproPTH and cleaved sequentially to proPTH and then the mature PTH(1-84) stored in secretory granules. The dominant regulator of secretion is extracellular ionized calcium acting on the calcium-sensing receptor (CaSR), a G-protein-coupled receptor on the chief-cell surface. When calcium is high, CaSR activation suppresses PTH release; when calcium falls, the brake is released and PTH secretion rises, producing the characteristic steep inverse sigmoidal curve between serum calcium and PTH. The cloning of the CaSR provided the molecular basis for this set point. Calcitriol feeds back to reduce PTH gene transcription, while phosphate and the magnesium status of the gland provide additional modulation. PTH circulates as the intact 1-84 hormone together with carboxyl-terminal fragments, which has implications for how the hormone is measured and interpreted.

Clinical relevance

The inverse calcium-PTH relationship is the conceptual basis for interpreting paired serum calcium and PTH measurements and for understanding parathyroid physiology in health. This entry describes the normal regulatory physiology and is not intended to direct diagnosis or treatment.

History

Parathyroid hormone was identified and characterized over the twentieth century as the principal calcium-raising hormone, with its sequence and biosynthetic pathway worked out and reviewed across decades of endocrine research. A pivotal advance came in 1993 when Brown and colleagues cloned the extracellular calcium-sensing receptor from bovine parathyroid tissue, giving a molecular explanation for how the gland reads the ambient calcium concentration and adjusts secretion.

Key figures

• John T. Potts
• Edward M. Brown

Seminal works

• potts-2005
• brown-1993
• murray-2005

Frequently asked questions

What controls how much PTH is secreted?

Extracellular ionized calcium is the dominant control: acting through the calcium-sensing receptor, high calcium suppresses PTH secretion and low calcium stimulates it, giving an inverse relationship. Calcitonin's role aside, calcitriol and phosphate provide additional modulation.

What is the calcium-sensing receptor?

It is a G-protein-coupled receptor on parathyroid chief cells, cloned in 1993, that detects extracellular calcium and sets the gland's secretory response to it.