Sustained signalling by PTH modulates IP3 accumulation and IP3 receptors through cyclic AMP junctions.
Sustained signalling by PTH modulates IP3 accumulation and IP3 receptors through cyclic AMP junctions.
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DOI：
10.1242/jcs.163071
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发表时间：
2015-01-15
影响因子：
4
通讯作者：
Taylor CW
中科院分区：
文献类型：
--
作者：
Meena A;Tovey SC;Taylor CW
甲状旁腺激素 (PTH) 通过 1 型 PTH 受体 (PTH1R) 刺激腺苷酸环化酶，并增强卡巴胆碱诱发的 Ca2+ 信号，从而刺激肌醇 1,4,5-三磷酸 (IP3) 的形成。我们证实，在表达 PTH1R 的 HEK 细胞中，PTH(1-34) 的急性刺激可增强卡巴胆碱诱发的 Ca2+ 释放。这是由局部递送的环 AMP (cAMP) 介导的，但不受蛋白激酶 A (PKA) 的抑制、cAMP 激活的交换蛋白、cAMP 磷酸二酯酶 (PDE) 或腺苷酸环化酶的实质性抑制的影响。 PTH(1-34) 的持续刺激会导致 PTH1R-腺苷酸环化酶信号复合物的内化，但在 cAMP 信号连接内将 cAMP 传递至 IP3R 的后果尚不清楚。在这里，我们表明，使用 PTH(1-34) 或不引起受体内化的 PTH 类似物持续刺激会减少增强的 Ca2+ 信号，并减弱卡巴胆碱引起的胞质 IP3 的增加。用 NKH477 持续刺激直接激活腺苷酸环化酶或使用 cAMP 的膜渗透类似物 8-Br-cAMP 持续刺激后，获得了类似的结果。这些反应独立于 PKA，并且不受腺苷酸环化酶显着抑制的影响。在用 PTH(1-34) 长时间刺激期间，过度活跃的 cAMP 信号传导连接（其中 cAMP 以饱和浓度直接递送至其靶标）介导 IP3R 的敏化和更缓慢发展的 IP3 积累抑制。
Parathyroid hormone (PTH) stimulates adenylyl cyclase through type 1 PTH receptors (PTH1R) and potentiates the Ca2+ 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 Ca2+ 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 Ca2+ 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.
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影响因子：
7.3
作者：
Pantazaka, Evangelia;Taylor, Emily J. A.;Taylor, Colin W.
通讯作者：
Taylor, Colin W.
影响因子：
7.3
作者：
Tovey, SC;Goraya, TA;Taylor, CW
通讯作者：
Taylor, CW
影响因子：
14.8
作者：
Ferrandon, Sebastien;Feinstein, Timothy N.;Castro, Marian;Wang, Bin;Bouley, Richard;Potts, John T.;Gardella, Thomas J.;Vilardaga, Jean-Pierre
通讯作者：
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DOI：
10.1073/pnas.0808750105
发表时间：
2008-10-28
影响因子：
11.1
作者：
Okazaki, Makoto;Ferrandon, Sebastien;Gardella, Thomas J.
通讯作者：
Gardella, Thomas J.
DOI：
10.1124/jpet.112.199752
发表时间：
2013-06-01
影响因子：
3.5
作者：
Cupp, Meghan E.;Nayak, Surendra K.;Thomsen, William J.
通讯作者：
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