Parathyroid Hormone Receptors

Parathyroid hormone and its cousin parathyroid hormone-related protein (PTHrP) are critical controllers of calcium and phosphorus balance. The receptors for these two hormones are under close scrutiny, because such understanding may facilitate development of antagonists for treatment of a number of important diseases, including osteoporosis and hypercalcemia associated with some types of cancer.

Two receptors have been identified that bind parathyroid hormone, one of which also binds PTHrP:

Type 1 parathyroid hormone receptor: Binds both parathyroid hormone and amino-terminal peptides of PTHrP. This molecule is a G protein-coupled receptor with seven transmembrane segments. The extracellular domain has six cysteine residues.

Binding of ligand to this receptor activates both adenylyl cyclase and phospholipase C systems, generating protein kinase A and protein kinase C signals, respectively. The cyclic AMP/protein kinase A pathway is predominant.

As might be expected from the actions of parathyroid hormone, the mRNA encoding the type 1 receptor is most abundant in bone (especially in chondrocytes at growth plates) and kidney. The mRNA is also expressed at lower levels in many other tissues, probably reflecting its use as a receptor for PTHrP.

Type 2 parathyroid hormone receptor: Binds parathyroid hormone, but shows very low affinity for PTHrP. This molecule is expressed in only a few tissues, and its structure and physiologic significance are poorly characterized. Like the type 1 receptor, it is coupled to adenylyl cyclase and ligand binding induces a rise in intracellular concentration of cyclic AMP.

Mutations in the type 1 receptor have been associated with rare human diseases. Jansen's metaphyseal chondroplasia is a syndrome of short limbed dwarfism resulting from a mutation that constitutively activates the receptor. Blomstrand's chondroplasia results from an inactivating mutation in the receptor gene, leading to a disease of early death with defective bone maturation, very similar to mice with targeted deletions of the PTHrP gene.

References and Reviews

• Mannstadt M, Juppner H, Gardella TJ: Receptors for PTH and PTHrH: Their biological importance and functional properties. Am J Physiol (Renal Physiology) 277:F665-F675, 1999.