A newly synthesized selective casein kinase I inhibitor, CK1-7, and affinity purification casein kinase I from bovine testis

Chijiwa, Takashi; Hagiwara, Masatoshi; Hidaka, Hiroyoshi

doi:10.1016/s0021-5198(19)56183-2

Cited by 8 publications

(10 citation statements)

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“…injections of IC261 (0.1-1 nmol) dose-dependently increased both withdrawal threshold and withdrawal latency of the hind paw ipsilateral to SNL (Figure 6 ). Another CK1 inhibitor CKI-7 [ 20 ] also showed similar effects (data not shown). These results suggest that blocking the CK1ε activity at the spinal level is effective in reducing mechanical allodynia and thermal hyperalgesia.…”

Section: Resultsmentioning

confidence: 61%

Upregulation of Casein Kinase 1∊ in Dorsal Root Ganglia and Spinal Cord after Mouse Spinal Nerve Injury Contributes to Neuropathic Pain

et al. 2009

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BackgroundNeuropathic pain is a complex chronic pain generated by damage to, or pathological changes in the somatosensory nervous system. Characteristic features of neuropathic pain are allodynia, hyperalgesia and spontaneous pain. Such abnormalities associated with neuropathic pain state remain to be a significant clinical problem. However, the neuronal mechanisms underlying the pathogenesis of neuropathic pain are complex and still poorly understood. Casein kinase 1 is a serine/threonine protein kinase and has been implicated in a wide range of signaling activities such as cell differentiation, proliferation, apoptosis, circadian rhythms and membrane transport. In mammals, the CK1 family consists of seven members (α, β, γ1, γ2, γ3, δ, and ε) with a highly conserved kinase domain and divergent amino- and carboxy-termini.ResultsPreliminary cDNA microarray analysis revealed that the expression of the casein kinase 1 epsilon (CK1ε) mRNA in the spinal cord of the neuropathic pain-resistant N- type Ca2+ channel deficient (Cav2.2-/-) mice was decreased by the spinal nerve injury. The same injury exerted no effects on the expression of CK1ε mRNA in the wild-type mice. Western blot analysis of the spinal cord identified the downregulation of CK1ε protein in the injured Cav2.2-/- mice, which is consistent with the data of microarray analysis. However, the expression of CK1ε protein was found to be up-regulated in the spinal cord of injured wild-type mice. Immunocytochemical analysis revealed that the spinal nerve injury changed the expression profiles of CK1ε protein in the dorsal root ganglion (DRG) and the spinal cord neurons. Both the percentage of CK1ε-positive neurons and the expression level of CK1ε protein were increased in DRG and the spinal cord of the neuropathic mice. These changes were reversed in the spinal cord of the injured Cav2.2-/- mice. Furthermore, intrathecal administration of a CK1 inhibitor IC261 produced marked anti-allodynic and anti-hyperalgesic effects on the neuropathic mice. In addition, primary afferent fiber-evoked spinal excitatory responses in the neuropathic mice were reduced by IC261.ConclusionsThese results suggest that CK1ε plays important physiological roles in neuropathic pain signaling. Therefore CK1ε is a useful target for analgesic drug development.

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Section: Resultsmentioning

confidence: 61%

Upregulation of Casein Kinase 1∊ in Dorsal Root Ganglia and Spinal Cord after Mouse Spinal Nerve Injury Contributes to Neuropathic Pain

et al. 2009

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“…This possibility is further reinforced by the observation that a third APH enzyme, APH(2″)-Ia is similarly inhibited by this compound (K i = 87.1±17.8 µM) [9] . However, the inhibition constants for CKI-7 are high, especially when compared to that obtained for the ePK CK1, which is an order of magnitude lower (K i = 8.5 µM) [22] . Nonetheless, at present CKI-7 is the only compound identified that is able to inhibit the ATP-binding site of several APH enzymes.…”

Section: Resultsmentioning

confidence: 63%

Crystal Structures of Two Aminoglycoside Kinases Bound with a Eukaryotic Protein Kinase Inhibitor

et al. 2011

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Antibiotic resistance is recognized as a growing healthcare problem. To address this issue, one strategy is to thwart the causal mechanism using an adjuvant in partner with the antibiotic. Aminoglycosides are a class of clinically important antibiotics used for the treatment of serious infections. Their usefulness has been compromised predominantly due to drug inactivation by aminoglycoside-modifying enzymes, such as aminoglycoside phosphotransferases or kinases. These kinases are structurally homologous to eukaryotic Ser/Thr and Tyr protein kinases and it has been shown that some can be inhibited by select protein kinase inhibitors. The aminoglycoside kinase, APH(3′)-IIIa, can be inhibited by CKI-7, an ATP-competitive inhibitor for the casein kinase 1. We have determined that CKI-7 is also a moderate inhibitor for the atypical APH(9)-Ia. Here we present the crystal structures of CKI-7-bound APH(3′)-IIIa and APH(9)-Ia, the first structures of a eukaryotic protein kinase inhibitor in complex with bacterial kinases. CKI-7 binds to the nucleotide-binding pocket of the enzymes and its binding alters the conformation of the nucleotide-binding loop, the segment homologous to the glycine-rich loop in eurkaryotic protein kinases. Comparison of these structures with the CKI-7-bound casein kinase 1 reveals features in the binding pockets that are distinct in the bacterial kinases and could be exploited for the design of a bacterial kinase specific inhibitor. Our results provide evidence that an inhibitor for a subset of APHs can be developed in order to curtail resistance to aminoglycosides.

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“…To allow a direct comparison of the effect of Wnt inhibition with the effects of Notch inhibition that we obtained from our in vitro data we used the same half embryo assay to investigate what effect Wnt attenuation has upon Notch target clock gene expression in the chick and mouse PSM. The first Wnt inhibitor used was CKI-7, an inhibitor of casein kinase 1 ( Chijiwa et al, 1989; Price, 2006 ), which is a key positive regulator of the canonical Wnt pathway acting downstream of Dishevelled ( Gao et al, 2002; Peters et al, 1999 ). Chick half embryo explants cultured for 4 h in the presence of CKI-7 (200 μM) led to a loss or severe down regulation of the PSM expression of a number of Wnt target genes, namely, cLef1 ( n = 33/34, Fig.…”

Section: Resultsmentioning

confidence: 99%

Interfering with Wnt signalling alters the periodicity of the segmentation clock

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Melton

et al. 2009

Developmental Biology

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Somites are embryonic precursors of the ribs, vertebrae and certain dermis tissue. Somite formation is a periodic process regulated by a molecular clock which drives cyclic expression of a number of clock genes in the presomitic mesoderm. To date the mechanism regulating the period of clock gene oscillations is unknown. Here we show that chick homologues of the Wnt pathway genes that oscillate in mouse do not cycle across the chick presomitic mesoderm. Strikingly we find that modifying Wnt signalling changes the period of Notch driven oscillations in both mouse and chick but these oscillations continue. We propose that the Wnt pathway is a conserved mechanism that is involved in regulating the period of cyclic gene oscillations in the presomitic mesoderm.

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A newly synthesized selective casein kinase I inhibitor, CK1-7, and affinity purification casein kinase I from bovine testis

Cited by 8 publications

References 0 publications

Upregulation of Casein Kinase 1∊ in Dorsal Root Ganglia and Spinal Cord after Mouse Spinal Nerve Injury Contributes to Neuropathic Pain

Upregulation of Casein Kinase 1∊ in Dorsal Root Ganglia and Spinal Cord after Mouse Spinal Nerve Injury Contributes to Neuropathic Pain

Crystal Structures of Two Aminoglycoside Kinases Bound with a Eukaryotic Protein Kinase Inhibitor

Interfering with Wnt signalling alters the periodicity of the segmentation clock

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