The newly synthesized selective Ca2+calmodulin dependent protein kinase II inhibitor KN-93 reduces dopamine contents in PC12h cells

Sumi, Mariko; Kiuchi, Kazutoshi; Ishikawa, Tomohiko; Ishii, Akira; Hagiwara, Masatoshi; Nagatsu, Toshiharu; Hidaka, Hiroyoshi

doi:10.1016/0006-291x(91)92031-e

Cited by 473 publications

(368 citation statements)

References 29 publications

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“…2 presents dose-response data for blockade of Pak activation by W-7 and several other structurally diverse, selective inhibitors that block different aspects of Ca 2ϩ signaling. The antagonists employed consisted of inhibitors of phospholipase C (PLC) (U-73122) (37), the intracellular Ca 2ϩ channel (TMB-8) (38), the Ca 2ϩ /CaM complex (trifluoperazine (TFP)) (39), and Ca 2ϩ /CaMactivated protein kinases (KN-93) (40). These compounds were chosen, in part, because of the availability of less active analogues to monitor possible nonspecific effects of the antagonists on cells.…”

Section: Effects Of Ca 2ϩ /Cam Antagonists On Activation Of the Paks mentioning

confidence: 99%

“…These compounds were chosen, in part, because of the availability of less active analogues to monitor possible nonspecific effects of the antagonists on cells. The less-active analogues of TFP, U-73122, and KN-93 are promethazine (PMZ), U-73343, and KN-92, respectively (37,39,40). All of the antagonists listed above blocked activation of the 63-and 69-kDa Paks in fMLP-stimulated neutrophils in a dosedependent manner at their effective pharmacological doses (Refs.…”

Section: Effects Of Ca 2ϩ /Cam Antagonists On Activation Of the Paks mentioning

confidence: 99%

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Antagonists of Calcium Fluxes and Calmodulin Block Activation of the p21-Activated Protein Kinases in Neutrophils

Lian

Crossley

Zhan

et al. 2001

The Journal of Immunology

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Neutrophils stimulated with fMLP or a variety of other chemoattractants that bind to serpentine receptors coupled to heterotrimeric G proteins exhibit rapid activation of two p21-activated protein kinases (Paks) with molecular masses of ∼63 and 69 kDa (γ- and α-Pak). Previous studies have shown that products of phosphatidylinositol 3-kinase and tyrosine kinases are required for the activation of Paks. We now report that a variety of structurally distinct compounds which interrupt different stages in calcium/calmodulin (CaM) signaling block activation of the 63- and 69-kDa Paks in fMLP-stimulated neutrophils. These antagonists included selective inhibitors of phospholipase C (1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione), the intracellular Ca2+ channel (8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate), CaM (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide; N-(4-aminobutyl)-5-chloro-1-naphthalenesulfonamide; trifluoperazine), and CaM-activated protein kinases (N-[2-(N-(chlorocinnamyl)-N-methylaminomethyl)phenyl]-N-[2-hydroxyethyl]-4-methoxybenzenesulfonamide). This inhibition was dose-dependent with IC50 values very similar to those that interrupt CaM-dependent reactions in vitro. In contrast, less active analogues of these compounds (1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-2,5-pyrrolidinedione; N-(6-aminohexyl)-1-naphthalenesulfonamide; N-(4-aminobutyl)-1-naphthalenesulfonamide; promethazine; 2-[N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzyl-amine]) did not affect activation of Paks in these cells. CaM antagonists (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide; trifluoperazine), but not their less-active analogues (N-(6-aminohexyl)-1-naphthalenesulfonamide; promethazine), were also found to block activation of the small GTPases Ras and Rac in stimulated neutrophils along with the extracellular signal-regulated kinases. These data strongly suggest that the Ca2+/CaM complex plays a major role in the activation of a number of enzyme systems in neutrophils that are regulated by small GTPases.

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Section: Effects Of Ca 2ϩ /Cam Antagonists On Activation Of the Paks mentioning

confidence: 99%

Section: Effects Of Ca 2ϩ /Cam Antagonists On Activation Of the Paks mentioning

confidence: 99%

Antagonists of Calcium Fluxes and Calmodulin Block Activation of the p21-Activated Protein Kinases in Neutrophils

Lian

Crossley

Zhan

et al. 2001

The Journal of Immunology

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“…However, it should be noted that a high concentration (40 m M) of KN-62 and KN-93 did not lead to any increase in attenuation, compared with 10 mM KN-62 and 5 mM KN-93 (Table 2). KN-62 and KN-93 were reported not to inhibit the activity of autophosphorylated CaM kinase II (25,26). The moderate inhibitory effects of KN-62 and KN-93 were possibly due to the conversion of GC from an insensitive to a sensitive state to ATP /DTTstimulation being partly mediated by autophosphorylated CaM kinase II, or an unknown protein kinase partly participating in the conversion from an insensitive to a sensitive state.…”

Section: Discussionmentioning

confidence: 99%

“…As shown in Table 2, staurosporine (1 m M), a general inhibitor of protein kinases, completely inhibited the conversion of GC from an insensitive to a sensitive state to ATP /DTT-stimulation. KN-62 (10 mM) and KN-93 (5 m M), specific inhibitors of CaM kinase II with a Ki value of 0.9 and 0.37 mM, respectively (25,26), had no effect on basal activity but attenuated the conversion of GC from an insensitive to a sensitive state to ATP /DTT-stimulation by 60% and 47%, respectively. On the other hand, preincubation with KN-62 and KN-93 had no effects on ANP-stimulated GC activity.…”

Section: Effects Of Protein Kinase Inhibitors On the Conversion Of Atmentioning

confidence: 99%

Regulation of Guanylate Cyclase by ATP and Dithiothreitol in Rat Lung Membrane: Involvement of an Insensitive and a Sensitive State to ATP / Dithiothreitol-Stimulation

Luo¹,

Takano²,

Asakawa³

2002

Japanese Journal of Pharmacology

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ABSTRACT-ATP/dithiothreitol (DTT)-stimulated guanylate cyclase (GC) in lung membrane was stimulated 18-fold by ATP and DTT, and both its activity and atrial natriuretic peptide (ANP)-stimulated GC activity were observed to be additive. ATP /DTT-stimulated GC was solubilized by octyl glucoside (OG) to examine the mechanism of ATP /DTT-stimulation. GC in OG-extracts was stimulated maximally 2.5-fold by both ATP, ATPgS or AMPPNP, and DTT. Preincubation of OG-extracts at 10°C with AMPPNP and DTT (1st-preincubation) converted GC to an insensitive state to stimulation by both ATP and DTT, and this conversion was partly inhibited by a protein phosphatase-1 inhibitor (10 -1000 nM okadaic acid). On the other hand, ANP-stimulated GC was not converted to an insensitive state to ANP /ATP-stimulation by the 1st-preincubation. Subsequent preincubation of OG-extracts at 10°C with both DTT and, ATP or ATPgS but not AMPPNP converted GC to a state sensitive to ATP /DTT-stimulation, and this conversion was partly inhibited by inhibitors of Ca 2+ /calmodulin-dependent protein kinase II . In contrast, the preincubation with KN-62 and KN-93 had no effect on ANP-stimulated GC activity. The results suggested that phosphorylation was involved in the regulation of ATP /DTT-stimulated GC sensitivity to ATP /DTTstimulation and that ATP /DTT-stimulated GC activity was likely to be a different type from ANP-stimulated GC activity.

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“…In order to determine whether CaMK activity is present in RAPHCs, we examined the effects of pretreatment with either 5 μM KN-93, or 5.5 μM KN-62, both selective CaMK inhibitors (Tokumitsu et al, 1990;Sumi et al, 1991;Davies et al, 2000). …”

Section: Ca 2+ /Cam-dependent Protein Kinase(s)mentioning

confidence: 99%

Slow motility in hair cells of the frog amphibian papilla: Myosin light chain-mediated shape change

Farahbakhsh

Narins

2008

Hearing Research

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Using video, fluorescence and confocal microscopy, quantitative analysis and modeling, we investigated intracellular processes mediating the calcium/calmodulin (Ca 2+ /CaM)-dependent slow motility in hair cells dissociated from the rostral region of amphibian papilla, one of the two auditory organs in frogs. The time course of shape changes in these hair cells during the period of pretreatment with several specific inhibitors, as well as their response to the calcium ionophore, ionomycin, were recorded and compared. These cells respond to ionomycin with a tri-phasic shape change: an initial phase of iso-volumetric length decrease; a period of concurrent shortening and swelling; and the final phase of increase in both length and volume. We found that both the myosin light chain kinase inhibitor, ML-7, and antagonists of the multifunctional Ca 2+ /CaM-dependent kinases, KN-62 and KN-93, inhibit the iso-volumetric shortening phase of the response to ionomycin. The type 1 protein phosphatase inhibitors, calyculin A and okadaic acid induce minor shortening on their own, but do not significantly alter the phase 1 response. However, they appear to counter effects of the inhibitors of Ca 2+ /CaM-dependent kinases. We hypothesize that an active actomyosin-based process mediates the iso-volumetric shortening in the frog rostral amphibian papillar hair cells.

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The newly synthesized selective Ca2+calmodulin dependent protein kinase II inhibitor KN-93 reduces dopamine contents in PC12h cells

Cited by 473 publications

References 29 publications

Antagonists of Calcium Fluxes and Calmodulin Block Activation of the p21-Activated Protein Kinases in Neutrophils

Antagonists of Calcium Fluxes and Calmodulin Block Activation of the p21-Activated Protein Kinases in Neutrophils

Regulation of Guanylate Cyclase by ATP and Dithiothreitol in Rat Lung Membrane: Involvement of an Insensitive and a Sensitive State to ATP / Dithiothreitol-Stimulation

Slow motility in hair cells of the frog amphibian papilla: Myosin light chain-mediated shape change

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