Soluble cyclase-mediated nuclear cAMP synthesis is sufficient for cell proliferation.
Soluble cyclase-mediated nuclear cAMP synthesis is sufficient for cell proliferation.
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可溶性环化酶介导的核 cAMP 合成足以促进细胞增殖。
DOI：
10.1073/pnas.2208749120
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发表时间：
2023-01-24
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
GPCR是哺乳动物受体的最大家族。通过cAMP的GsPCR信号传导起始于质膜（第一波），并在受体从细胞内区室内化后继续（第二波），其生理作用尚未明确确立。利用促甲状腺激素释放激素-甲状腺系统，我们发现，促甲状腺激素触发的内化依赖性积累的核cAMP介导的局部可溶性环化酶（sAC）激活，而不是cAMP扩散从胞质溶胶。我们提出了一个新的“cAMP信号传导的三波模型”，提出持续的cAMP（第二波）的作用是作为中间扩散因子进入细胞核并激活sAC的Ca 2+的动员。这种核SAC产生的cAMP（第三波）对于甲状腺细胞增殖是足够的和限速的。cAMP是许多生理过程中的关键参与者，传统上被认为仅来源于质膜（PM）。这种观点最近受到挑战的观察表明，在内化GsPCR可以维持信号从内体和/或trans-Golgi网络（TGN）。在这种新的观点中，在第一个PM产生的cAMP波之后，GsPCR和AC的内化产生了第二波，该第二波与负责触发特定生物反应的核转录事件严格相关。在这里，我们报告说，内源性表达的TSHR，一个典型的GsPCR，触发一个内化依赖性，钙介导的核sAC激活，驱动PKA激活和CREB磷酸化。药理学和遗传学sAC抑制，这并不影响胞浆cAMP水平，钝化核cAMP积累，PKA激活，和细胞增殖，而核sAC表达的增加显着增强细胞增殖。此外，使用新的核靶向光遗传学致动器，我们表明，光刺激的核cAMP合成可以通过激活PKA和CREB模拟TSH的增殖作用。因此，基于我们的研究结果，我们提出了一个新的三波模型，其中cAMP的“第三”波是由核sAC产生的。尽管位于PM（第一波）和内体/TGN（第二波）发生事件的下游，但核SAC产生的cAMP（第三波）对于甲状腺细胞增殖是足够的和限速的。
GPCRs are the largest family of mammalian receptors. GsPCRs signaling via cAMP initiates at the plasma membrane (first wave) and continues upon receptor internalization from an intracellular compartment (second wave), whose physiological role is not yet clearly established. Utilizing the TSHR-thyroid system, we show that TSH triggers an internalization-dependent accumulation of nuclear cAMP mediated solely by local soluble cyclase (sAC) activation, rather than cAMP diffusion from the cytosol. We present a new “three-wave model of cAMP signaling” proposing that the role of the sustained cAMP (second wave) is the mobilization of Ca2+ as an intermediate diffusible factor that enters the nucleus and activates sAC. This nuclear sAC-generated cAMP (third wave) is sufficient and rate-limiting for thyroid cell proliferation. cAMP, a key player in many physiological processes, was classically considered to originate solely from the plasma membrane (PM). This view was recently challenged by observations showing that upon internalization GsPCRs can sustain signaling from endosomes and/or the trans-Golgi network (TGN). In this new view, after the first PM-generated cAMP wave, the internalization of GsPCRs and ACs generates a second wave that was strictly associated with nuclear transcriptional events responsible for triggering specific biological responses. Here, we report that the endogenously expressed TSHR, a canonical GsPCR, triggers an internalization-dependent, calcium-mediated nuclear sAC activation that drives PKA activation and CREB phosphorylation. Both pharmacological and genetic sAC inhibition, which did not affect the cytosolic cAMP levels, blunted nuclear cAMP accumulation, PKA activation, and cell proliferation, while an increase in nuclear sAC expression significantly enhanced cell proliferation. Furthermore, using novel nuclear-targeted optogenetic actuators, we show that light-stimulated nuclear cAMP synthesis can mimic the proliferative action of TSH by activating PKA and CREB. Therefore, based on our results, we propose a novel three-wave model in which the “third” wave of cAMP is generated by nuclear sAC. Despite being downstream of events occurring at the PM (first wave) and endosomes/TGN (second wave), the nuclear sAC-generated cAMP (third wave) is sufficient and rate-limiting for thyroid cell proliferation.
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影响因子：
4.8
作者：
Christensen, AE;Selheim, F;Doskeland, SO
通讯作者：
Doskeland, SO
影响因子：
6.5
作者：
Harden, T. Kendall;Hicks, Stephanie N.;Sondek, John
通讯作者：
Sondek, John
影响因子：
16.6
作者：
Beautrait A;Paradis JS;Zimmerman B;Giubilaro J;Nikolajev L;Armando S;Kobayashi H;Yamani L;Namkung Y;Heydenreich FM;Khoury E;Audet M;Roux PP;Veprintsev DB;Laporte SA;Bouvier M
通讯作者：
Bouvier M
DOI：
10.1111/1440-1681.12756
发表时间：
2017-12-01
影响因子：
2.9
作者：
Chen, Hui;Chan, Hsiao Chang
通讯作者：
Chan, Hsiao Chang
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：
Vilardaga, Jean-Pierre