H 89 2HCl (Synonyms: 5Isoquinolinesulfonamide, Protein Kinase Inhibitor H89)

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.