Parathyroid Hormone Receptor

To characterize normal and pathologic systemic calcium homeostasis, it is pertinent to clarify some aspects of the cloned PTH receptor.117 Apart from the classic targets of PTH in bone and kidney, the receptor has been demonstrated in fibroblasts, chondrocytes, lymphocytes, smooth muscle cells, and fat cells. This allows PTH to induce hypotension and bowel relaxation and to influence chronotropism and inotropism of the heart in addition to its classic actions on bone turnover and calcium, phosphate, and vitamin D metabolism in the kidney. The receptor also binds PTHrP with similar efficiency. Because PTHrP exerts a variety of hitherto partially clarified functions, studies on the common PTH-PTHrP receptor and its actions are hampered by difficulties in determining the biologically relevant agonist. Activation of the PTH receptor's cAMP-generating capacity requires PTH amino acids 1-24, and PTH 1-34 is essentially as potent as the full-length peptide.118 However, various PTH fragments may activate other second messenger systems of the receptor with variable efficiency, whereby complex modes of differential interactions may exist. Moreover, specialized binding sites for midregional and carboxyterminal PTH sequences of unknown functional significance may occur.119

The PTH receptor belongs to the growing family of peptide receptors characterized by seven transmembrane domains and G protein coupling. Expression of this receptor is sensitive to PTH, and prolonged exposure to the ligand can reduce the number of available receptors, whereby target cell functions are less effectively activated.120 HPT of uremia is a striking example in this phenomenon, with its frequently profound elevation of intact serum PTH levels and comparably modest rise in serum calcium values. Internalization and partial recycling of the receptor protein are the mechanisms for this modulation.121 Decreased affinity for PTH and desensitization of the cAMP response may modulate the peripheral actions of PTH.122 Other substances such as glucocorticoids as well as vitamin A and D metabolites may interfere with PTH receptor expression, although their in vivo actions in humans remain to be established. Inherited variants of pseudohypoparathyroidism may be caused by dysfunctions in the PTH receptor, its associated G proteins, and different second messenger systems such as adenylate cyclase and phospholipase C.123

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