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Parathyroid hormone increases the sensitivity of inositol trisphosphate receptors by a mechanism that is independent of cyclic AMP
Author(s) -
Tovey Stephen C,
Goraya Tasmina A,
Taylor Colin W
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705011
Subject(s) - endocrinology , ibmx , medicine , carbachol , parathyroid hormone , receptor , adenylyl cyclase , inositol phosphate , inositol , chemistry , stimulation , second messenger system , inositol trisphosphate , phosphodiesterase , calcium , forskolin , biology , biochemistry , enzyme
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+ ]. PTH potentiated the Ca 2+ release evoked by a cell‐permeant analogue of inositol 1,4,5‐trisphosphate (Ins P 3 BM). Prolonged incubation with Ins P 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 Ins P 3 ‐sensitive Ca 2+ pool. Responses to PTH were unaffected by disruption of the cytoskeleton. The EC 50 for carbachol‐evoked Ca 2+ release and Ins P 3 formation were indistinguishable (∼40 μ M ), consistent with even the highest concentrations of carbachol generating insufficient Ins P 3 to release the entire Ins P 3 ‐sensitive Ca 2+ pool. 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. 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. We conclude that PTH potentiates the Ca 2+ release evoked by receptors that stimulate Ins P 3 formation by sensitizing Ins P 3 receptors through a cyclic AMP‐independent mechanism.British Journal of Pharmacology (2003) 138 , 81–90. doi: 10.1038/sj.bjp.0705011