H-89 2HCl is A potent and selective camp-dependent protein kinase A inhibitor with IC50 value of 48 nM, showing weak inhibition of PKG,PKC,Casein kinase and other kinases[1]. H-89 2HCl causes different modifications in protein phosphorylation, all of which have potential regulatory relationships with cAMP/PKA[2].
H-89 2HCl (30μM) significantly inhibited camp-dependent phosphorylation of histone IIh and forskolin-induced neurite outgrowth in PC12D cells[1]. H-89 2HCl (1-2 μM) significantly slows the repriming rate in rat skinned fibres, most likely due to it deleteriously affecting the T-system potential. H-89 2HCl (10-100 μM) inhibits net Ca2+ uptake by the SR and affectes the Ca32-sensitivity of the contractile apparatus in rat skinned fibres[4]. The PKA inhibitor H-89 2HCl effectively inhibited the CM-or PTHRP-mediated increase in UCP1 protein levels and phosphorylation of PKA substrate in ccRCC cells[6].
Trehalase (Treh) hydrolyzes trehalose to generate glucose. Pheromone biosynthesis activating neuropeptide (PBAN) treatment triggered HaTreh1 and HaTreh2 activities in the isolated PGs. However, the activities of HaTreh1 and HaTreh2 triggered by PBAN were offset by H-89 2HCl, the specific inhibitor of protein kinase A (PKA). Furthermore, the H-89 2HCl treatment significantly decreased the phosphorylation level of Trhe2, which was induced by PBAN[3]. The PKA inhibitor H-89 2HCl potently blocked oncosphere larval motility, as well as the motility of other life stages, although other inhibitors of the PKA pathway were not effective[7]. H-89 2HCl (0.2 mg/100g) significantly increases seizure latency and threshold in PTZ-treated animals. H-89 2HCl (0.05, 0.2 mg/100 g) prevents the epileptogenic activity of bucladesine with significant increase of seizure latency and seizure threshold[5].
References:
[1]: Chijiwa T, Mishima A, et,al. Inhibition of forskolin-induced neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), of PC12D pheochromocytoma cells. J Biol Chem. 1990 Mar 25;265(9):5267-72. PMID: 2156866.
[2]: Davis MA, Hinerfeld D, et,al. Proteomic analysis of rat liver phosphoproteins after treatment with protein kinase inhibitor H89 (N-(2-[p-bromocinnamylamino-]ethyl)-5-isoquinolinesulfonamide). J Pharmacol Exp Ther. 2006 Aug;318(2):589-95. doi: 10.1124/jpet.105.100032. Epub 2006 May 10. PMID: 16687476.
[3]: Zhang B, Zhang Y, et,al. Trehalase is required for sex pheromone biosynthesis in Helicoverpa armigera. Insect Mol Biol. 2022 Jun;31(3):334-345. doi: 10.1111/imb.12762. Epub 2022 Feb 4. PMID: 35084068.
[4]: Blazev R, Hussain M, Bakker AJ, Head SI, Lamb GD. Effects of the PKA inhibitor H-89 on excitation-contraction coupling in skinned and intact skeletal muscle fibres. J Muscle Res Cell Motil. 2001;22(3):277-86. doi: 10.1023/a:1012289526618. PMID: 11763200.
[5]: Hosseini-Zare MS, Salehi F, Seyedi SY, Azami K, Ghadiri T, Mobasseri M, Gholizadeh S, Beyer C, Sharifzadeh M. Effects of pentoxifylline and H-89 on epileptogenic activity of bucladesine in pentylenetetrazol-treated mice. Eur J Pharmacol. 2011 Nov 30;670(2-3):464-70. doi: 10.1016/j.ejphar.2011.09.026. Epub 2011 Sep 21. PMID: 21946102.
[6]: Wei G, Sun H, et,al. The thermogenic activity of adjacent adipocytes fuels the progression of ccRCC and compromises anti-tumor therapeutic efficacy. Cell Metab. 2021 Oct 5;33(10):2021-2039.e8. doi: 10.1016/j.cmet.2021.08.012. Epub 2021 Sep 10. PMID: 34508696.
[7]: Preza M, Guarnaschelli I, et,al. Inhibitors of protein kinases A and C impair the motility of oncospheres of the model tapeworm Hymenolepis microstoma. Mol Biochem Parasitol. 2021 Nov;246:111423. doi: 10.1016/j.molbiopara.2021.111423. Epub 2021 Sep 22. PMID: 34562553.
H-89 2HCl 是一种有效的选择性 camp 依赖性蛋白激酶 A 抑制剂,IC50 值为 48 nM,对 PKG、PKC、酪蛋白激酶和其他激酶表现出较弱的抑制作用 [1]。 H-89 2HCl引起不同的蛋白磷酸化修饰,均与cAMP/PKA[2]具有潜在的调控关系。
H-89 2HCl (30μM) 显着抑制 PC12D 细胞中组蛋白 IIh 的营依赖性磷酸化和毛喉素诱导的神经突生长[1]。 H-89 2HCl (1-2 μM) 显着减慢大鼠皮肤纤维的重新启动速率,很可能是因为它有害地影响了 T 系统的潜力。 H-89 2HCl (10-100 μM) 抑制 SR 对 Ca2+ 的净摄取,并影响大鼠皮肤纤维中收缩装置的 Ca32 敏感性[4]。 PKA抑制剂H-89.2HCl有效抑制ccRCC细胞中CM-或PTHRP介导的UCP1蛋白水平升高和PKA底物磷酸化[6]。
海藻糖酶 (Treh) 水解海藻糖生成葡萄糖。信息素生物合成激活神经肽 (PBAN) 处理触发了分离的 PG 中的 HaTreh1 和 HaTreh2 活性。然而,由 PBAN 触发的 HaTreh1 和 HaTreh2 的活性被蛋白激酶 A (PKA) 的特异性抑制剂 H-89.2HCl 所抵消。此外,H-89 2HCl 处理显着降低了由 PBAN[3] 诱导的 Trhe2 的磷酸化水平。 PKA 抑制剂 H-89 2HCl 有效地阻断了肿瘤球幼虫的运动,以及其他生命阶段的运动,尽管 PKA 通路的其他抑制剂无效[7]。 H-89 2HCl (0.2 mg/100g) 显着增加 PTZ 治疗动物的癫痫发作潜伏期和阈值。 H-89 2HCl (0.05, 0.2 mg/100 g) 可抑制布克拉地辛的致癫痫活性,显着增加癫痫发作潜伏期和癫痫发作阈值[5]。