Parathyroid hormone pathways

Most GPCRs interact with and activate more than one G-protein subfamily, e.g., with Gs plus Gq/n (histamine H2, parathyroid hormone and calcitonin recqrtors), Gs plus G (luteinising hormone receptor, 32-adrenoceptor) or Gq/11 plus G12/13 (thromboxane A2, angiotensin ATb endothelin ETA receptors). Some receptors show even broader G-protein coupling, e.g., to Gi, Gq/n plus Gi n ( protease-activated receptors, lysophosphatidate and sphingosine-1-phosphate receptors) or even to all four G-protein subfamilies (thyrotropin receptor). This multiple coupling results in multiple signaling via different pathways and in a concerted reaction of the cell to the stimulus. 

Parathyroid hormone (PTH) regulates calcium levels in blood and bone remodeling. The activation domain of that 84-amino acid polypeptide locates around the N-terminal (1-34 amino acids). Parathyroid hormone receptor is a typical G-protein coupled receptor, which is coupled to both adenyl cyclase/cAMP and PLCy/IP3/cytosolic Ca2+ intracellular signaling pathways. In order to identify the structural elements involved in the peptide hormone binding and signal initiation, Chorev et al. employed a photoaffinity scanning approach. The N-terminal amino acids were successively deleted or modified and the new N-terminus was replaced for photoreactive Bpa. The most active peptide ana-... 

Y. Nabuchi, E. Fujiwara, H. Kuboniwa, Y. Asoh, H. Ushio, The Stability and Degradation Pathway of Recombinant Human Parathyroid Hormone Deamidation of Asparaginyl Residue and Peptide Bond Cleavage at Aspartyl and Asparaginyl Residues , Pharm. Res. 1997, 14, 1685-1690. 

Ion transport pathways across the luminal and basolateral membranes of the distal convoluted tubule cell. As in all tubular cells, Na+/K+ ATPase is present in the basolateral membrane. NCC is the primary sodium and chloride transporter in the luminal membrane. (R, parathyroid hormone [PTH] receptor.)... 

Swarthout JT, D Alonzo RC, Selvamurugan N, Partridge NC. Parathyroid hormone-dependent signaling pathways regulating genes in bone cells. Gene. 2002 282 1-17. 

Carvalho, R.S., Scott, J.E., Suga, D.M., et al. (1994) Stimulation of signal transduction pathways in osteoblasts by mechanical strain potentiated by parathyroid hormone. Journal of Bone and Mineral Research 9 999-1011... 

Miyauchi A, Notoya K, Mikuni-TakagakiY, Takagi Y, Goto M, Miki Y, Takano-Yamamoto T, Jinnai K,Takashashi K, Kumegawa M, Chihara K, FujitaT. Parathyroid hormone-activated volume-sensitive calcium influx pathways in mechanically loaded osteocytes. J Biol Chem. 2000 275(5) 3335-3342. 

Bone is a relatively dynamic organ that undergoes significant turnover that is, hone resorption and deposition it is broken down hy osteoclasts and rebuilt by osteoblasts. Besides an adequate supply of calcium, a close cooperation is required between these two types of cell. Complex signalling pathways achieve proper rates of growth and differentiation these pathways include the action of several hormones, including parathyroid hormone (PTH), vitamin D, growth hormone, steroids and calcitonin, as well as several cytokines. 

Sox4 a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins, such as syndecan binding protein (syntenin). The protein may also function in the apoptosis pathway leading to cell death as well as to tumorigenesis and may mediate downstream effects of parathyroid hormone (PTH) and PTH-related protein (PTHrP) in bone development. 

PTHrP is structurally related to parathyroid hormone (PTH). In contrast to PTH, which is exclusively expressed in and secreted by the parathyroid gland, PTHrP is expressed and released by vascular smooth muscle cells and endothelial cells but not by ventricular myocytes. PTH and PTHrP are potent dilators and exert positive chronotropic and inotropic effects (reviewed by Halapas40). PTHrP activates adenyl cyclase and increases c-AMP levels with subsequent activation of PKA/PKC dependent pathways.41,42... 

Drugs currently used to treat osteoporosis are classified into those that inhibit osteoclastic bone resorption (including bisphos-phonates, denosumab, and selective estrogen receptor modulators) and those that stimulate bone formation by osteoblasts (parathyroid hormone and derivatives, such as teriparatide). Strontium ranelate may have a dual effect. Other drugs being tested in clinical trials include inhibitors of cathepsin K (an osteoclastic enzyme critical for bone resorption) and of sclerostin (a negative modulator of the Wnt pathway) [21],... 

Two cell lines that are often used as a model for the proximal nephron are the porcine cell hne, LLC-PKj and the OK cell line from the opossum kidney. Both of these cell hnes lack expression of the enzyme fructose-1, 6-bisphosphatase, rendering them incapable of glu-coneogenesis, a key metabohc pathway in proximal nephron cells [4]. In addihon, LLC-PKj cells are not responsive to parathyroid hormone, and lack a probenedd-sensitive organic anion transporter [131]. 

Nabuchi Y, Fujiwara E, Kuboniwa H, et al. (1997). The stability and degradation pathway of recombinant human parathyroid hormone Deamidation of asparaginyl residue and peptide bond cleavage at aspartyl and asparaginyl residues. Pharm. Res. 14 1685-1690. 

Gesty-Palmer D, Chen M, Reiter E, Ahn S, Nelson CD, Wang S, Eckhardt AE, Cowan CL, Spumey RE, Luttrell LM, Lefkowitz RJ (2006) Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERKl/2 activation. J Biol Chem 281 (16) 10856-10864... 

The passive transport pathway is nonsaturable and paracellular. It occurs throughout the small intestine and is unaffected by calcium status or parathyroid hormone (PTH). It is relatively independent of 1,25(0H)2D3, although this metabolite has been foimd by some investigators to increase the permeability of the paracellular pathway. A substantial amoimt of calcium is absorbed by passive transport in the ileum due to the relatively slow passage of food through this section of the intestine. The amoimt of calcium absorbed by passive transport will be proportional to the intake and bioavailability of calcium consumed. 

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