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Sustained signalling by PTH modulates IP3 accumulation and IP3 receptors through cyclic AMP junctions.

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Meena, Abha 
Tovey, Stephen C 
Taylor, Colin W 


Parathyroid hormone (PTH) stimulates adenylyl cyclase through type 1 PTH receptors (PTH1R) and potentiates the Ca(2+) signals evoked by carbachol, which stimulates formation of inositol 1,4,5-trisphosphate (IP3). We confirmed that in HEK cells expressing PTH1R, acute stimulation with PTH(1-34) potentiated carbachol-evoked Ca(2+) release. This was mediated by locally delivered cyclic AMP (cAMP), but unaffected by inhibition of protein kinase A (PKA), exchange proteins activated by cAMP, cAMP phosphodiesterases (PDEs) or substantial inhibition of adenylyl cyclase. Sustained stimulation with PTH(1-34) causes internalization of PTH1R-adenylyl cyclase signalling complexes, but the consequences for delivery of cAMP to IP3R within cAMP signalling junctions are unknown. Here, we show that sustained stimulation with PTH(1-34) or with PTH analogues that do not evoke receptor internalization reduced the potentiated Ca(2+) signals and attenuated carbachol-evoked increases in cytosolic IP3. Similar results were obtained after sustained stimulation with NKH477 to directly activate adenylyl cyclase, or with the membrane-permeant analogue of cAMP, 8-Br-cAMP. These responses were independent of PKA and unaffected by substantial inhibition of adenylyl cyclase. During prolonged stimulation with PTH(1-34), hyperactive cAMP signalling junctions, within which cAMP is delivered directly and at saturating concentrations to its targets, mediate sensitization of IP3R and a more slowly developing inhibition of IP3 accumulation.



Ca2+ signalling, Cyclic AMP, Inositol trisphosphate receptor, Parathyroid hormone, Adenylyl Cyclases, Calcium, Calcium Signaling, Carbachol, Colforsin, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Cytosol, HEK293 Cells, Humans, Inositol 1,4,5-Trisphosphate, Inositol 1,4,5-Trisphosphate Receptors, Parathyroid Hormone, Receptor, Parathyroid Hormone, Type 1

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J Cell Sci

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The Company of Biologists
Biotechnology and Biological Sciences Research Council (BB/L000075/1)
Wellcome Trust (101844/Z/13/Z)
Supported by the Wellcome Trust (101844) and the Biotechnology and Biological Sciences Research Council (L000075). AM was supported in part by the Central Institute of Medicinal and Aromatic Plants (CSIR), Lucknow, India.