Parathyroid hormone increases the sensitivity of inositol trisphosphate receptors by a mechanism that is independent of cyclic AMP
Parathyroid hormone increases the sensitivity of inositol trisphosphate receptors by a mechanism that is independent of cyclic AMP
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DOI：
10.1038/sj.bjp.0705011
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发表时间：
2003-01-01
影响因子：
7.3
通讯作者：
Taylor, CW
中科院分区：
文献类型：
--
作者：
Tovey, SC;Goraya, TA;Taylor, CW
1负载呋喃2的HEK-293细胞稳定表达人1型甲状旁腺激素（PTH）受体。PTH增强卡巴胆碱引起的Ca 2+动员>4倍，而本身不增加细胞内[Ca 2 +]。2 PTH增强1，4，5-三磷酸肌醇（InsP（3）BM）的细胞渗透性类似物引起的Ca 2+释放。3与InsP（3）BM长时间孵育与PTH联合最大浓度的卡巴胆碱一样有效地排空Ca 2-储存，表明PTH并没有增加InsP（3）敏感的Ca 2+池的大小。4对PTH的反应不受细胞内毒素破坏的影响。5卡巴胆碱诱发的Ca 2-释放和InsP（3）形成的EC 50是不可区分的（类似于40 μ M），这与甚至最高浓度的卡巴胆碱产生的InsP 3不足以释放整个InsP（3）-敏感性Ca 2+池一致。6环AMP依赖性蛋白激酶A（PKA），使用H89或CMIQ，不影响PTH. 7 SQ 22536或DDA对卡巴胆碱诱发的Ca 2+信号的增强。腺苷酸环化酶的抑制剂，抑制PTH诱发的环AMP的形成和IBMX，环核苷酸磷酸二酯酶的抑制剂，增加环AMP的量后检测到的PTH刺激。这些药物均不影响PTH最大或次最大浓度对Ca 2+信号的增强作用。8我们得出结论，PTH通过环AMP非依赖性机制，通过敏化InsP（3）受体，增强刺激InsP（3）形成的受体诱发的Ca 2+释放。
1 In fura 2-loaded HEK-293 cells stably expressing human type 1 parathyroid hormone (PTH) receptors. PTH potentiated the Ca2+ mobilization evoked by carbachol by >4 fold without itself increasing the intracellular [Ca2+].2 PTH potentiated the Ca2+ release evoked by a cell-permeant analogue of inositol 1,4,5-trisphosphate (InsP(3)BM).3 Prolonged incubation with InSP3BM emptied the Ca2- 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 Ca2+ pool.4 Responses to PTH were unaffected by disruption of the cytoskeleton.5 The EC50 for carbachol-evoked Ca2- release and InsP(3) formation were indistinguishable (similar to40 muM), consistent with even the highest concentrations of carbachol generating insufficient InsP3 to release the entire InsP(3)-sensitive Ca2+ pool.6 Inhibition of cyclic AMP-dependent protein kinase A (PKA), using H89 or CMIQ, did not affect potentiation of carbachol-evoked Ca2+ 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 Ca2+ signals by maximal or submaximal concentrations of PTH.8 We conclude that PTH potentiates the Ca2+ release evoked by receptors that stimulate InsP(3) formation by sensitizing InsP(3) receptors through a cyclic AMP-independent mechanism.