A G protein–coupled, IP3/protein kinase C pathway controlling the synthesis of phosphaturic hormone FGF23

Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes

“…Activation of Gq signaling promotes insulin secretion mainly through 2 pathways: the DAG/PKC pathway and the IP 3 /Ca 2+ pathway (46,47). We monitored PKC activity using phosphoserine PKC substrate antibody (48). Antibody reactivity to a number of proteins was increased in Kcnj11 -/-βCL1 compared with parental control cells under basal conditions ( Figure 3E), indicating that the DAG/PKC pathway is enhanced in Kcnj11 -/-βCL1.…”

A paternally inherited non‐sense variant c.424G>T (p.G142*) in the first exon of XLαs in an adult patient with hypophosphatemia and osteopetrosis

“…This study indicated that XLαs could mimic Gsα in vivo . In XLαs knockout (XLKO) mice, hyperphosphatemia, hypocalcemia, as well as increased concentrations of serum PTH and substantially reduced fibroblast growth factor‐23 (FGF23) levels were found compared to WT mice . It has been suggested that XLαs mediates the stimulatory action of PTH in skeletal FGF23 production through IP3/PKC pathway .…”

“…In XLαs knockout (XLKO) mice, hyperphosphatemia, hypocalcemia, as well as increased concentrations of serum PTH and substantially reduced fibroblast growth factor‐23 (FGF23) levels were found compared to WT mice . It has been suggested that XLαs mediates the stimulatory action of PTH in skeletal FGF23 production through IP3/PKC pathway . In these mice, PTH‐induced cAMP excretion in the urine was modestly increased, while basal and PTH‐stimulated production of inositol 1,4,5‐trisphosphate (IP3), which is the second messenger produced by Gq/11 signaling, was repressed in renal proximal tubules from XLKO mice, indicating XLαs enhances Gq/11 signaling to mediate the renal actions of PTH .…”

Osteocytic FGF23 and Its Kidney Function

“…Furthermore, Notch signaling, which can be mediated by pro-inflammatory cytokines such as TNF-α ( 50 ), has been described by Tamamura et al, to positively regulate FGF23 expression which colocalizes with Notch signaling downstream targets, Notch, and Hes1 in mouse osteocytes and UMR-106 osteoblastic cells ( 51 ). A study also identified a potential new pathway mediated by G protein–IP3/PKC events to control FGF23 production ( 52 ). It was shown that the ablation of the extra-large Gα subunit (XLαs) or Gq/11α in osteocyte-like Ocy454 cells activated IP3/PKC and stimulated the MAPK/ERK1/2 pathway leading to FGF23 induction ( 52 ).…”

“…A study also identified a potential new pathway mediated by G protein–IP3/PKC events to control FGF23 production ( 52 ). It was shown that the ablation of the extra-large Gα subunit (XLαs) or Gq/11α in osteocyte-like Ocy454 cells activated IP3/PKC and stimulated the MAPK/ERK1/2 pathway leading to FGF23 induction ( 52 ). It is assumed that the trigger of the IP3/PKC/MAPK pathway is controlled by a G protein-coupled receptor which remains to be identified ( Figure 1 ).…”