PTH produces its effects on target cells by stimulating the synthesis of second messengers, most notably cyclic adenosine monophosphate (cyclic AMP) by the enzyme adenylate cyclase (see Plate 3-9). This intracellular second messenger activates protein kinase A, which catalyzes the phosphorylation of several cellular proteins and thereby modifies their activity.

Although all of the targets of phosphorylation have not been identified, they likely include proteins involved in the transport of calcium and phosphate, as well as proteins that regulate gene transcription. To activate adenylyl cyclase, PTH binds to specific heptahelical receptor molecules on the surface of the cell. The first segment of PTH, containing 34 of the 84 amino acids in the hormone, is the only component required for binding and activating receptor molecules; the function, if any, of the remainder of the peptide is unknown (see Plate 3-1).

Adenylate cyclase is a separate molecule on the inner surface of the cell membrane (see Plate 3-9). However, for adenylate cyclase to convert adenosine triphosphate (ATP) to cyclic AMP, it must interact with Gα_s, which is activated by the PTH-receptor complex. Gα_s is one component of the heterotrimeric G protein, Gs, and can bind and hydrolyze guanosine triphosphate (GTP). In the “off” state guanosine diphosphate (GDP) is bound to Gα_s, which enhances its affinity for the βγ subunit. Ligand-bound receptors interact with the heterotrimeric Gs and promote release of GDP, thereby allowing GTP to bind to Gα_s. Gα_s-GTP dissociates from the βγ subunit and in the “on” state is then able to stimulate adenylyl cyclase. After a very brief period of time the GTP is hydrolyzed to GDP, and the Gα_s-GDP molecule then reassociates with βγ to end a cycle of hormone activation. As noted earlier, expression or function of Gα_s is reduced in PHP type 1, which impairs receptor activation of adenylyl cyclase. Cyclic AMP is rapidly degraded by intracellular phosphodiesterase enzymes, although some of it also leaks out of the cell. In the kidney, cyclic AMP produced under the influence of PTH leaks out of proximal renal tubule cells and is excreted in the urine.