Parathyroid hormone increases the sensitivity of inositol trisphosphate receptors by a mechanism that is independent of cyclic AMP.
1 In fura 2-loaded HEK-293 cells stably expressing human type 1 parathyroid hormone (PTH) receptors, PTH potentiated the Ca(2+) mobilization evoked by carbachol by >4 fold without itself increasing the intracellular [Ca(2+)]. 2 PTH potentiated the Ca(2+) release evoked by a cell-permeant analogue of inositol 1,4,5-trisphosphate (InsP(3)BM). 3 Prolonged incubation with InsP(3)BM emptied the Ca(2+) stores as effectively as PTH in combination with a maximal concentration of carbachol, indicating that PTH did not increase the size of the InsP(3)-sensitive Ca(2+) pool. 4 Responses to PTH were unaffected by disruption of the cytoskeleton. 5 The EC(50) for carbachol-evoked Ca(2+) release and InsP(3) formation were indistinguishable (approximately 40 microM), consistent with even the highest concentrations of carbachol generating insufficient InsP(3) to release the entire InsP(3)-sensitive Ca(2+) pool. 6 Inhibition of cyclic AMP-dependent protein kinase A (PKA), using H89 or CMIQ, did not affect potentiation of carbachol-evoked Ca(2+) signals by PTH. 7 SQ22536 or DDA, inhibitors of adenylyl cyclase, inhibited PTH-evoked cyclic AMP formation and IBMX, an inhibitor of cyclic nucleotide phosphodiesterase, increased the amount of cyclic AMP detected after stimulation by PTH. None of these drugs affected the potentiation of Ca(2+) signals by maximal or submaximal concentrations of PTH. 8 We conclude that PTH potentiates the Ca(2+) release evoked by receptors that stimulate InsP(3) formation by sensitizing InsP(3) receptors through a cyclic AMP-independent mechanism.
Tovey
Stephen C
SC
Department of Pharmacology, Tennis Court Road, Cambridge CB2 1PD, UK.
Goraya
Tasmina A
TA
Taylor
Colin W
CW
D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010281:Parathyroid Hormone / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*
D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010281:Parathyroid Hormone; D018160:Receptors, Cytoplasmic and Nuclear; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D002118:Calcium