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• W1991032022 abstract "We have developed several kinds of protein kinase inhibitors, which are classified as isoquinolinesulfonamides and characterized as ATP competitive inhibitors of Ser/Thr protein kinases. These include H9, H89, KN62, and 1-(5-isoquinolinesulfonyl)-homopiperazine (HA-1077) against protein kinase C (PKC), protein kinase A, Ca2+/calmodulin-dependent protein kinase II, and Rho-kinase, respectively, and they have been used widely to confirm the involvement of the target protein kinase in biological or physiological reaction(s). In some cases, inhibitors have predicted the involvement of the target protein kinase in cell or tissue before its precise mechanism or its effector was defined. On a clinical level, we developed the Rho-kinase inhibitor HA-1077 as an anti-spastic that effectively suppresses the spasm of cerebral arteries after subarachnoid hemorrhage. We have improved HA-1077 to obtain (S)-(+)-2-methyl-1-[(4-methyl-5-isoquinoline)sulfonyl]-homopiperazine (H-1152P), which is a more selective inhibitor of Rho-kinase, with a Ki value of 1.6 nM for Rho-kinase, 630 nM for protein kinase A, and 9270 nM for PKC. This inhibitor suppressed the phosphorylation of myristoylated alanine-rich C-kinase substance (MARCKS) in neuronal cells stimulated with lysophosphatidic acid, whose phosphorylation site was confirmed to be the Ser159 residue, using a phosphorylation site-specific antibody. In contrast, phorbol 12-myristate 13-acetate-induced phosphorylation of MARCKS was scarcely inhibited by H-1152P. Furthermore, lysophosphatidic acid-stimulated phosphorylation in neuronal cells was characterized as a C3 toxin-sensitive event. Our results show that the Rho-kinase inhibitor targets a protein with a well-known function, MARCKS in neuronal cells. Although MARCKS is widely recognized as a substrate of PKC, our results raise the possibility that MARCKS is a target protein of Rho-kinase in neuronal cells. In this review, we address the possible role of Rho-kinase in neuronal functions, using the Rho-kinase specific inhibitor H-1152P." @default.
• W1991032022 created "2016-06-24" @default.
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• W1991032022 date "2002-02-01" @default.
• W1991032022 modified "2023-10-18" @default.
• W1991032022 title "The novel and specific Rho-kinase inhibitor (S)-(+)-2-methyl-1-[(4-methyl-5-isoquinoline)sulfonyl]-homopiperazine as a probing molecule for Rho-kinase-involved pathway" @default.
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• W1991032022 doi "https://doi.org/10.1016/s0163-7258(02)00191-2" @default.
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