Heterotrimeric G proteins in the control of parathyroid hormone actions

Abstract

Parathyroid hormone (PTH) is a key regulator of skeletal physiology and calcium and phosphate homeostasis. It acts on bone and kidney to stimulate bone turnover, increase the circulating levels of 1,25 dihydroxyvitamin D and calcium, and inhibit the reabsorption of phosphate from the glomerular filtrate. Dysregulated PTH actions contribute to or are the cause of several endocrine disorders. This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11. Genetic mutations affecting the activity or expression of the alpha-subunit of Gs, encoded by the GNAS complex locus, are responsible for several human diseases for which the clinical findings result, at least partly, from aberrant PTH signaling. Here we review the bone and renal actions of PTH with respect to the different signaling pathways downstream of these G proteins, as well as the disorders caused by GNAS mutations.

Small intestine resection increases oxalate and citrate transporter expression and calcium oxalate crystal formation in rat hyperoxaluric kidneys

“…The main signaling pathway underlying the PTH receptor is PKA activation [ 19 ]. We, thus, examined whether the PKA pathway was involved in changes in Slc26a6 or NaDC-1 expression.…”

“…The increased Slc26a6 and NaDC-1 expressions in the PTH+Oxa group were similar to those seen in the Oxa and PTH groups, respectively. The main signaling pathway underlying the PTH receptor is PKA activation [19]. We, thus, examined whether the PKA pathway was involved in changes in Slc26a6 or NaDC-1 expression.…”

CFTR-mediated anion secretion in parathyroid hormone-treated Caco-2 cells is associated with PKA and PI3K phosphorylation but not intracellular pH changes or Na+/K+-ATPase abundance

“…In the renal epithelial cells, PTH1R was found to exert downstream signals via G s /cAMP/PKA- and PI3K-dependent pathways [ 27 , 28 ]. Although PTH1R can be coupled with G q/11 [ 29 ], PTH did not alter [Ca] i level in Caco-2 cells as determined by Fluo-4 probe, suggesting that the G q/11 /[Ca] i pathway was not induced in the stimulation of enterocytes by PTH. Similarly, osteoblasts, the well-known target of PTH, can also respond to PTH in G q/11 /[Ca] i -independent manner [ 29 ].…”

Expression of Phosphatonin-Related Genes in Sheep, Dog and Horse Kidneys Using Quantitative Reverse Transcriptase PCR

“…For example, PTH1R may couple with a number of different stimulatory G proteins, which may activate different secondary messenger pathways, and PTH1R on the apical and basolateral membranes of the renal tubular epithelial cell may have different roles [ 46 ]. In addition, the function of PTH1R on sodium-phosphate co-transporter expression in renal tubular epithelial cells is modulated by the binding of PTH1R to NHERF1 (sodium hydrogen exchanger regulatory factor 1) and activation of the phospholipase C pathway, which ultimately leads to NPT2a internalization from the cell membrane [ 47 , 48 ]. As such, there are a number of physiological intermediates between PTH1R and the sodium-phosphate co-transporters, suggesting that direct correlation may not be appropriate.…”