H-89 Explained

H-89 is a protein kinase inhibitor with greatest effect on protein kinase A (PKA).[1] H-89, derived from H-8 (N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide),[2] was initially believed to act specifically as an inhibitor of PKA,[3] being 30 times more potent than H-8 at inhibiting PKA and 10 times less potent at inhibiting protein kinase G. It achieves this through competitive inhibition of the adenosine triphosphate (ATP) site on the PKA catalytic subunit.[4] However, subsequent work has suggested a variety of additional effects such as inhibition of other protein kinases (values of 80, 120, 135, 270, 2600 and 2800 nM for S6K1, MSK1, PKA, ROCKII, PKBα and MAPKAP-K1b respectively),[5] and direct inhibition of various potassium currents.[6]

In addition to its use in studying mechanisms of cell signalling, H-89 has also been used experimentally in vivo. H-89 has been shown to increase the threshold and latency of pentylenetetrazol-induced seizures [7] and decrease morphine withdrawal symptoms in mice.[8]

Notes and References

  1. Marunaka . Yoshinori . Niisato . Naomi . H89, an inhibitor of protein kinase A (PKA), stimulates Na+ transport by translocating an epithelial Na+ channel (ENaC) in fetal rat alveolar type II epithelium . Biochemical Pharmacology . 66 . 6 . 1083–9 . 2003 . 12963496 . 10.1016/S0006-2952(03)00456-8.
  2. Hidaka. H.. Inagaki. M.. Kawamoto. S.. Sasaki. Y.. 1984-10-09. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry. 23. 21. 5036–5041. 0006-2960. 6238627. 10.1021/bi00316a032.
  3. Chijiwa. T.. Mishima. A.. Hagiwara. M.. Sano. M.. Hayashi. K.. Inoue. T.. Naito. K.. Toshioka. T.. Hidaka. H.. 1990-03-25. 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. The Journal of Biological Chemistry. 265. 9. 5267–5272. 10.1016/S0021-9258(19)34116-X. 0021-9258. 2156866. free.
  4. Murray . A. J. . Pharmacological PKA Inhibition: All May Not Be What It Seems . Science Signaling . 1 . 22 . re4 . 2008 . 18523239 . 10.1126/scisignal.122re4 .
  5. Lochner . A. . Moolman . J. A. . The Many Faces of H89: A Review . Cardiovascular Drug Reviews . 24 . 3–4 . 261–74 . 2006 . 17214602 . 10.1111/j.1527-3466.2006.00261.x . free .
  6. Pearman. Charles. Kent. William. Bracken. Nicolas. Hussain. Munir. August 2006. H-89 inhibits transient outward and inward rectifier potassium currents in isolated rat ventricular myocytes. British Journal of Pharmacology. 148. 8. 1091–1098. 10.1038/sj.bjp.0706810. 0007-1188. 1752020. 16799649.
  7. Hosseini-Zare . Mahshid Sadat . Salehi . Forouz . Seyedi . Seyedeh Yalda . Azami . Kian . Ghadiri . Tahereh . Mobasseri . Mohammad . Gholizadeh . Shervin . Beyer . Cordian . Sharifzadeh . Mohammad . Effects of pentoxifylline and H-89 on epileptogenic activity of bucladesine in pentylenetetrazol-treated mice . European Journal of Pharmacology . 670 . 2–3 . 464–70 . 2011 . 21946102 . 10.1016/j.ejphar.2011.09.026 .
  8. Seyedi . Seyedeh Y. . Salehi . Forouz . Payandemehr . Borna . Hossein . Sara . Hosseini-Zare . Mahshid S. . Nassireslami . Ehsan . Yazdi . Behnoosh B. . Sharifzadeh . Mohammad . Dual effect of cAMP agonist on ameliorative function of PKA inhibitor in morphine-dependent mice . Fundamental & Clinical Pharmacology . 28 . 4 . 445–54 . 2014 . 24033391 . 10.1111/fcp.12045 . 36095599 . free .

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