KN-62, 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazi ne, a specific inhibitor of Ca2+/calmodulin-dependent protein kinase II.

Tokumitsu, Hiroshi; Chijiwa, Takashi; Hagiwara, Masatoshi; Mizutani, Akihiro; Terasawa, Motomu; Hidaka, Hiroyoshi

doi:10.1016/s0021-9258(19)39565-1

Cited by 587 publications

(36 citation statements)

References 36 publications

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“…In order to investigate a role for CamK in the regulation of BDNF mRNA in vivo, we have examined the effect of 1-[N,O-bis(5isoquinoline-sulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62) treatment prior to kainic acid-induced seizures. KN-62 has been reported to specifically inhibit CamKII and IV activity (Tokumitsu et al, 1990;Enslen & Soderling, 1994). Our results suggest that multiple pathways exist for the induction of BDNF mRNA in vivo at least some of which are mediated in a CamKII/IV-dependent manner.…”

Section: Introductionmentioning

confidence: 57%

Attenuation of the seizure‐induced expression of BDNF mRNA in adult rat brain by an inhibitor of calcium/calmodulin‐dependent protein kinases

Murray¹,

Hayes²,

Gall³

et al. 1998

Eur J of Neuroscience

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We have examined the potential involvement of calcium/calmodulin-dependent protein kinases in the regulation of brain-derived neurotrophic factor mRNA in vivo following kainic acid (kainate)-induced seizure activity by in situ hybridization. KN-62, a specific inhibitor of calcium/calmodulin-dependent protein kinase type II and IV, blocked the characteristic induction of brain-derived neurotrophic factor mRNA seen following seizure activity. This blockade was specific to calcium/calmodulin-dependent protein kinase type II and IV as inhibitors of both protein kinase C and cAMP-dependent protein kinase had no effect. Inhibition of brain-derived neurotrophic factor mRNA increases varied between brain regions; an almost complete inhibition was seen throughout cortical regions, whereas only partial inhibitory effects were noted within hippocampus. A similar inhibition of increased c-fos mRNA was observed throughout cortical, hippocampal and diencephalic regions. The two predominant brain-derived neurotrophic factor transcripts induced by kainate, containing exons I or III, were differentially affected by KN-62. The cortical induction of exon I was blocked by KN-62, whereas exon III was not, providing additional evidence for the differential regulation of individual brain-derived neurotrophic factor transcripts and demonstrating that inhibition of brain-derived neurotrophic factor induction was not due to general blockade of seizure activity throughout the neocortex. These data implicate calcium/calmodulin-dependent protein kinase type II or IV in the regulation of brain-derived neurotrophic factor mRNA in vivo and suggest regionally specific mechanisms occur throughout the brain.

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Section: Introductionmentioning

confidence: 57%

Attenuation of the seizure‐induced expression of BDNF mRNA in adult rat brain by an inhibitor of calcium/calmodulin‐dependent protein kinases

Murray¹,

Hayes²,

Gall³

et al. 1998

Eur J of Neuroscience

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“…CaMKII regulates transmitter metabolism in sympathetic neurons (Cahill and Perlman, 1987), and PKC contributes to internalization and desensitization of muscarinic receptors (Liles et al, 1986); hence both are candidates. Treatment of recipient neuroblastoma cells with KN-62, a specific membranepermeant inhibitor of CaMKII (Tokumitsu et al, 1990), prevented the appearance of LTS (n ϭ 4) but did not inhibit the rise in cGMP with muscarinic stimulation (Fig. 7A).…”

Section: How Is Lts Maintained?mentioning

confidence: 97%

Patch Cramming Reveals the Mechanism of Long-Term Suppression of Cyclic Nucleotides in Intact Neurons

Trivedi

Krämer

2002

J. Neurosci.

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To understand cyclic nucleotide dynamics in intact cells, we used the patch-cramming method with cyclic nucleotide-gated channels as real-time biosensors for cGMP. In neuroblastoma and sympathetic neurons, both muscarinic agonists and nitric oxide (NO) rapidly elevate cGMP. However, muscarinic agonists also elicit a long-term (2 hr) suppression (LTS) of subsequent cGMP responses. Muscarinic agonists elevate cGMP by triggering Ca2+ mobilization, which activates NO synthase to produce NO, leading to the activation of soluble guanylate cyclase (sGC). Here we examine the mechanism of LTS. Experiments using direct intracellular cGMP injection demonstrate that enhancement of phosphodiesterase (PDE) activity, rather than depression of sGC activity, is responsible for LTS. Biochemical measurements show that both cGMP and cAMP content is suppressed, consistent with the involvement of a nonselective PDE. Application of pharmacological agents that alter Ca2+ mobilization from intracellular stores and experiments involving injection of the Ca2+ chelator BAPTA show that Ca2+ mobilization is necessary and sufficient for LTS induction but also show that LTS maintenance is Ca2+-independent. Protein phosphatase injection reverses LTS, and specific inhibitors of Ca2+/calmodulin kinase II (CaMKII) prevent induction and inhibit maintenance. The switch between the Ca2+ dependence of LTS induction to the Ca2+ independence of LTS maintenance is consistent with CaMKII autophosphorylation, similar to proposed mechanisms of hippocampal long-term potentiation. Because the molecular machinery underlying LTS is common to many cells, LTS may be a widespread mechanism for long-term silencing of cyclic nucleotide signaling.

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“…To address whether CaM kinase may mediate the effects of CaM on PLC␤ activity, 1321N1 cells were treated with CaMKII inhibitors, 30 M KN-93 or 2 M KN-62 (26,27). In 1321N1 cells pre-treated with CaMKII inhibitors for 30 min, there was no effect on basal or carbachol-stimulated IP hydrolysis (Fig.…”

Section: Table I Specific Interaction Of Plc␤ 3 With Cammentioning

confidence: 99%

Calmodulin Is a Phospholipase C-β Interacting Protein

McCullar

Larsen

Millimaki

et al. 2003

Journal of Biological Chemistry

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Phospholipase C-beta 3 (PLC beta 3) is an important effector enzyme in G protein-coupled signaling pathways. Activation of PLC beta 3 by G alpha and G beta gamma subunits has been fairly well characterized, but little is known about other protein interactions that may also regulate PLC beta 3 function. A yeast two-hybrid screen of a mouse brain cDNA library with the amino terminus of PLC beta 3 has yielded potential PLC beta 3 interacting proteins including calmodulin (CaM). Physical interaction between CaM and PLC beta 3 is supported by a positive secondary screen in yeast and the identification of a CaM binding site in the amino terminus of PLC beta 3. Co-precipitation of in vitro translated and transcribed amino- and carboxyl-terminal PLC beta 3 revealed CaM binding at a putative amino-terminal binding site. Direct physical interaction of PLC beta 3 and PLC beta 1 isoforms with CaM is supported by pull-down of both isoenzymes with CaM-Sepharose beads from 1321N1 cell lysates. CaM inhibitors reduced M1-muscarinic receptor stimulation of inositol phospholipid hydrolysis in 1321N1 astrocytoma cells consistent with a physiologic role for CaM in modulation of PLC beta activity. There was no effect of CaM kinase II inhibitors, KN-93 and KN-62, on M1-muscarinic receptor stimulation of inositol phosphate hydrolysis, consistent with a direct interaction between PLC beta isoforms and CaM.

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KN-62, 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazi ne, a specific inhibitor of Ca2+/calmodulin-dependent protein kinase II.

Cited by 587 publications

References 36 publications

Attenuation of the seizure‐induced expression of BDNF mRNA in adult rat brain by an inhibitor of calcium/calmodulin‐dependent protein kinases

Attenuation of the seizure‐induced expression of BDNF mRNA in adult rat brain by an inhibitor of calcium/calmodulin‐dependent protein kinases

Patch Cramming Reveals the Mechanism of Long-Term Suppression of Cyclic Nucleotides in Intact Neurons

Calmodulin Is a Phospholipase C-β Interacting Protein

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