KN-62 is a selective calmodulin-dependent protein kinase II (CaMKII) inhibitor and also a potent non-competitive P2X7 receptor antagonist[1][2]. CaMKII is a serine/threonine kinase that plays a critical role in calcium signaling by phosphorylating various substrates involved in neurotransmission, muscle contraction, and other cellular processes[3]. P2X7 is an ATP-gated ion channel belonging to the P2X receptor family, which is activated by high concentrations of extracellular ATP and mediates inflammatory responses and cell death[4]. KN-62 is usually used in the research of neural signal transduction, inflammatory response and tumor metastasis mechanisms[5].
In vitro, treatment of tamoxifen-resistant MCF-7 cells with KN-62 (3μM; 24h) inhibits ATP-induced calcium influx, cell proliferation and migration, and reduces small extracellular vesicle secretion and CD63 expression[6].
In vivo, KN-62 (1μg/site; i.c.v.) reversed the ZnCl₂-induced reduction in immobility time in the tail suspension test in Swiss mice[7].
References:
[1] Schweitzer ES, Sanderson MJ, Wasterlain CG. Inhibition of regulated catecholamine secretion from PC12 cells by the Ca2+/calmodulin kinase II inhibitor KN-62. J Cell Sci. 1995;108 ( Pt 7):2619-2628.
[2] Gargett CE, Wiley JS. The isoquinoline derivative KN-62 a potent antagonist of the P2Z-receptor of human lymphocytes. Br J Pharmacol. 1997;120(8):1483-1490.
[3] Reyes Gaido OE, Nkashama LJ, Schole KL, et al. CaMKII as a Therapeutic Target in Cardiovascular Disease. Annu Rev Pharmacol Toxicol. 2023;63:249-272.
[4] Sluyter R. The P2X7 Receptor. Adv Exp Med Biol. 2017;1051:17-53.
[5] Pellicena P, Schulman H. CaMKII inhibitors: from research tools to therapeutic agents. Front Pharmacol. 2014;5:21.
[6] Park M, Kim J, Phuong NTT, et al. Involvement of the P2X7 receptor in the migration and metastasis of tamoxifen-resistant breast cancer: effects on small extracellular vesicles production. Sci Rep. 2019;9(1):11587.
[7] Manosso LM, Moretti M, Ribeiro CM, Gonçalves FM, Leal RB, Rodrigues ALS. Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation. Prog Neuropsychopharmacol Biol Psychiatry. 2015;59:59-67.
KN-62是一种选择性钙调蛋白依赖性蛋白激酶II（CaMKII）抑制剂，同时是强效非竞争性P2X7受体拮抗剂[1][2]。CaMKII是一种丝氨酸/苏氨酸激酶，通过磷酸化参与神经信号传导、肌肉收缩及其他细胞过程的多种底物，在钙信号转导中发挥关键作用[3]。P2X7是P2X受体家族的ATP门控离子通道，由细胞外高浓度ATP激活，介导炎症反应和细胞死亡[4]。KN-62通常用于神经信号转导、炎症反应及肿瘤转移机制的研究[5]。
在体外，KN-62（3μM；24小时）处理他莫昔芬耐药的MCF-7细胞可抑制ATP诱导的钙内流、细胞增殖和迁移，并减少小细胞外囊泡分泌及CD63表达[6]。
在体内，KN-62（1μg/位点；脑室内注射）可逆转ZnCl₂诱导的Swiss小鼠在悬尾实验中不动时间的缩短[7]。