The signaling initiated by the parathyroid hormone (PTH) plays a central role in calcium (Ca2+) and phosphate homeostasis. In response to low Ca2+, the hormone is secreted from the parathyroid glands; high Ca2+ levels activate the Ca2+ sensing receptor whose signaling inhibits its secretion. In the kidney, PTH regulates Ca2+ and phosphate reabsorption: specifically, it increases Ca2+ reabsorption leading to increased release of the metal into the circulation; it diminishes phosphate absorption
leading to excretion of the mineral. It exerts both catabolic and anabolic effects on bone; the former leads to Ca2+ and phosphate release while the latter renders the hormone an anti-osteoporosis agent. PTH also promotes production of the active form of vitamin D3 which leads to increase in circulating Ca2+, hence the negative effect vitamin D3 has on PTH activity. In the renal epithelial cells, the vanilloid transient potential receptor TRP5 and TRP6 are involved in Ca2+ influx and under the control of PTH and vitamin D. Upon entry, the metal ion is sequestered by calbindin buffers and then extruded through the concerted action of transporters such as PMCA1 and NCX1. PTH employs a G-protein coupled receptor (GPCR) that belongs to the B group: the parathyroid hormone receptor 1 (Pthr1). The related parathyroid hormone-like hormone (PTHrP), also signals via Pth1 but promotes distinct effects. The crystal structure of the extracellular domain (ECD) of Pth1r in complex with PTH has been solved; the PTH alpha helix is sandwiched within a hydrophobic groove formed by a three-layer alpha-beta-beta/alpha ECD fold click to access the structure page . The binding of PTH to Pth1r triggers conformational changes promoting coupling to heterotrimeric G proteins for which the receptor acts as a GTP exchange factor (GEF) catalyzing the exchange of GDP bound to the G alpha subunit, for GTP. The active, GTP-bound G alpha subunit can now dissociate from the complex to interact with its effectors; the G alpha will signal for as long as it is associated with GTP. Pthr1 couples to two types of G protein mediated signaling: the Galphas mediated signaling which promotes cAMP synthesis and further activates the protein kinase A (PKA) pathway and it appears to be the main downstream route, and the Galphaq mediated signaling which activates phospholipase C resulting in production of IP3 which triggers Ca2+ release from intracellular stores and DAG which activates the protein kinase C (PKC) pathway. G protein specific kinases such as Adrbk1 (Grk2) phosphorylate the receptor prompting its recognition by beta-arrestin proteins resulting in receptor desensitization and subsequent internalization; beta-arrestin bound receptors are sterically precluded from coupling to G proteins. In the case of PTH signaling, beta-arrestins may provide scaffolding functions and the same might be true for the beta/gamma dimers of heterotrimeric G proteins. It is believed that the beta/gamma dimers which interact with Pth1r, do not dissociate and instead allow for the interaction of the receptor with other partners. The intracellular tail of the receptor offers many binding sites; partners include calpain, calmodulin, the light chain subunit of the cytoplasmic dynein complex Dynlt1 but the role these interactions play in vivo is still to be determined. Important partners for Pth1r are the scaffolding proteins Slc9a3r known as the NHERF family of regulators of sodium/phosphate co-transporters type 2. The regulators contain two tandem N-terminal PDZ domains . Pth1r preferentially binds to the PDZ1 domain of Slc9a3r1 (NHERF1) and to the PDZ2 domain of Slc9a3r2 (NHE RF2). The interaction biases the receptor between the two G-protein mediated pathways promoting the Galphaq and, depending on the identity of the regulator, either inhibiting or having no effect on Galphas. The function of type 2 sodium/phosphate co-transporters is regulated by correct membrane targeting and retrieval/endocytosis. Ezrin, a FERM domain containing scaffold interacts with both Pth1r and Slc9a3r1; the ezrin-Slc3a9r1 scaffold is important for both the correct membrane targeting and for the Pth/Pth1r mediated endocytosis of Slc34a1 transporter, known as Npt2a. Ezrin is an AKAP (A kinase anchor protein) for PKA pathway. Activation of PKA and phosphorylation of Slc9a3r1 promotes disassembly of a ternary Slc34a1-Slc9a3r1-ezrin complex with subsequent internalization and degradation of the transporter. The effect of PTH on phosphate reabsorption is very fast; a similar, but rather slow response is elicited by the fibroblast growth factor 23 signaling. FGF23 also negatively regulates PTH and vitamin D3 production. An intricate interaction between PTH, vitamin D3 and FGF23 pathways underlies calcium and/or phosphate homeostasis.To see the ontology report for annotations, Gviewer and download, click here ....(less)
