cAMP signaling through protein kinase A and Epac2 induces substance P release in the rat spinal cord.
cAMP signaling through protein kinase A and Epac2 induces substance P release in the rat spinal cord.
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DOI：
10.1016/j.neuropharm.2021.108533
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发表时间：
2021-05-15
影响因子：
4.7
通讯作者：
Marvizon JC
中科院分区：
文献类型：
--
作者：
Chen W;McRoberts JA;Ennes HS;Marvizon JC
用神经激肽1受体（NK 1 R）内化法测定大鼠脊髓片P物质释放，发现P物质释放受腺苷酸环化酶（AC）激活剂forskolin、蛋白激酶A（PKA）激活剂6-Bnz-cAMP和8-Br-cAMP以及cAMP激活的交换蛋白激活剂（Epac）8-pCPT-2-O-Me-cAMP（CPTOMe-cAMP）的诱导。相反，AC和PKA抑制剂减少P物质释放诱导的电刺激背根。因此，cAMP信号通路介导背角中的P物质释放。Forskolin和6-Bnz-cAMP的作用不与NMDA诱导的P物质释放相加，并被NMDA受体阻断剂MK-801降低。在培养的背角神经元中，毛喉素增加NMDA诱导的Ca 2+内流和NMDA受体NR 1和NR 2B亚基的磷酸化。因此，cAMP诱导的P物质释放是由NMDA受体PKA激活磷酸化介导的。电压门控性Ca ~（2+）通道也参与cAMP诱导的P物质释放，但TRPV 1和TRPA 1不参与。PKA的激活是毛喉素和三种cAMP类似物的作用所必需的。Epac 2促进了毛喉素和CPTOMe-cAMP的作用，通过Raf -促分裂原活化的蛋白激酶途径进行信号传导以激活Ca 2+通道。Epac 1抑制剂诱导NK 1 R内化独立于P物质释放。在对疼痛具有潜在敏感性的大鼠中，6-Bnz-cAMP的作用不变，而毛喉素的作用由于Epac 2的刺激作用的丧失而降低。因此，在疼痛超敏反应期间，cAMP诱导的P物质释放减少。cAMP控制P物质（SP）释放的拟议途径图。腺苷酸环化酶（AC）产生cAMP，然后激活蛋白激酶A，Epac 1和Epac 2。PKA激活Cav2.2通道（N型）、NMDA受体（NMDAR）和mTOR，所有这些都有助于SP释放。Epac 2通过Rap、Raf-1激酶、MEK和MAPK信号传导，导致Cav 1、Cav2.1和Cav3.2通道（L、P、Q和T型）的激活，这也有助于SP释放。Epac 1直接抑制NK 1 R内化。
Using neurokinin 1 receptor (NK1R) internalization to measure of substance P release in rat spinal cord slices, we found that it was induced by the adenylyl cyclase (AC) activator forskolin, by the protein kinase A (PKA) activators 6-Bnz-cAMP and 8-Br-cAMP, and by the activator of exchange protein activated by cAMP (Epac) 8-pCPT-2-O-Me-cAMP (CPTOMe-cAMP). Conversely, AC and PKA inhibitors decreased substance P release induced by electrical stimulation of the dorsal root. Therefore, the cAMP signaling pathway mediates substance P release in the dorsal horn. The effects of forskolin and 6-Bnz-cAMP were not additive with NMDA-induced substance P release and were decreased by the NMDA receptor blocker MK-801. In cultured dorsal horn neurons, forskolin increased NMDA-induced Ca2+ entry and the phosphorylation of the NR1 and NR2B subunits of the NMDA receptor. Therefore, cAMP-induced substance P release is mediated by the activating phosphorylation by PKA of NMDA receptors. Voltage-gated Ca2+ channels, but not by TRPV1 or TRPA1, also contributed to cAMP-induced substance P release. Activation of PKA was required for the effects of forskolin and the three cAMP analogs. Epac2 contributed to the effects of forskolin and CPTOMe-cAMP, signaling through a Raf - mitogen-activated protein kinase pathway to activate Ca2+ channels. Epac1 inhibitors induced NK1R internalization independently of substance P release. In rats with latent sensitization to pain, the effect of 6-Bnz-cAMP was unchanged, whereas the effect of forskolin was decreased due to the loss of the stimulatory effect of Epac2. Hence, substance P release induced by cAMP decreases during pain hypersensitivity. Diagram of the proposed pathways by which cAMP controls substance P (SP) release. Adenylyl cyclase (AC) produces cAMP, which then activates protein kinase A, Epac1 and Epac2. PKA activates Cav2.2 channels (N type), NMDA receptors (NMDAR) and mTOR, all of which contribute to SP release. Epac2 signals through Rap, Raf-1 kinase, MEK and MAPK, leading to the activation of Cav1, Cav2.1 and Cav3.2 channels (L, P, Q and T types), which also contribute to SP release. Epac1 directly inhibits NK1R internalization.
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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：
4.8
作者：
Courilleau, Delphine;Bisserier, Malik;Lezoualc'h, Frank
通讯作者：
Lezoualc'h, Frank
影响因子：
7.3
作者：
Chen, Haijun;Tsalkova, Tamara;Chepurny, Oleg G.;Mei, Fang C.;Holz, George G.;Cheng, Xiaodong;Zhou, Jia
通讯作者：
Zhou, Jia
影响因子：
8.8
作者：
Célèrier, E;Rivat, C;Simonnet, G
通讯作者：
Simonnet, G
DOI：
10.1124/jpet.104.079855
发表时间：
2005-04-01
影响因子：
3.5
作者：
Gavva, NR;Tamir, R;Treanor, JJS
通讯作者：
Treanor, JJS