scholarly journals Altered synaptic adaptation and gain in sensory circuits of the casein kinase 1 delta (CK1dT44A) mouse model of migraine

2019 ◽  
Author(s):  
Pratyush Suryavanshi ◽  
Punam Sawant Pokam ◽  
KC Brennan
Keyword(s):  
Steady State ◽  
Cortical Neurons ◽  
Casein Kinase ◽  
Local Network ◽  
Casein Kinase 1 ◽  
Thermal Pain ◽  
Readily Releasable Pool ◽  
Short Stimulus

AbstractMigraine is a very common and disabling neurological disorder that remains poorly understood at the cellular and circuit level. Transgenic mice harboring a mutation in casein kinase 1 delta (CK1dT44A) represent the first animal model of non-hemiplegic migraine. These mice have decreased sensory thresholds to mechanical and thermal pain after treatment with the migraine trigger nitroglycerin; and an increased susceptibility to cortical spreading depression (CSD), which models the migraine aura. In this study, we investigated cellular and synaptic mechanisms within sensory cortical circuits that might underlie the migraine relevant phenotypes of CK1dT44A mice, using in vitro and in vivo whole cell electrophysiology. Surprisingly we found that at resting state, CK1dT44A neurons exhibited hyperpolarized membrane potentials, due to increased tonic inhibition. Despite this reduction in baseline excitability, CK1dT44A neurons fired action potentials more frequently in response to current injection. And despite similar synaptic and dendritic characteristics to wild type neurons, excitatory but not inhibitory CK1dT44A synapses failed to adapt to high frequency short-stimulus trains, resulting in elevated steady state excitatory currents. The increased steady state currents were attributable to an increased replenishment rate of the readily releasable pool, providing a presynaptic mechanism for the CK1dT44A phenotype. Finally, during in vivo experiments, CK1dT44A animals showed increased duration and membrane potential variance at ‘cortical up states’, showing that the intrinsic and synaptic changes we observed have excitatory consequences at the local network level. In conclusion excitatory sensory cortical neurons and networks in CK1dT44A animals appear to exhibit decreased adaptation and increased gain that may inform the migraine phenotype.

scholarly journals Generation of strong casein kinase 1 inhibitor of Arabidopsis thaliana

2019 ◽  
Author(s):  
Ami N Saito ◽  
Hiromi Matsuo ◽  
Keiko Kuwata ◽  
Azusa Ono ◽  
Toshinori Kinoshita ◽  
...  
Keyword(s):  
Bromine Atom ◽  
Casein Kinase ◽  
In Planta ◽  
Vitro Assay ◽  
Casein Kinase 1 ◽  
Yeast Fungi ◽  
Genes Encoding ◽  
Period Lengthening

AbstractCasein kinase 1 (CK1) is an evolutionarily conserved protein kinase among eukaryotes. Studies on yeast, fungi, and animals have revealed that CK1 plays roles in divergent biological processes. By contrast, the collective knowledge regarding the biological roles of plant CK1 lags was behind those of animal CK1. One of reasons for this is that plants have more multiple genes encoding CK1 than animals. To accelerate the research for plant CK1, a strong CK1 inhibitor that efficiently inhibits multiple members of CK1 proteins in vivo (in planta) is required. Here, we report a novel strong CK1 inhibitor of Arabidopsis (AMI-331). Using a circadian period-lengthening activity as estimation of the CK1 inhibitor effect in vivo, we performed a structure-activity relationship (SAR) study of PHA767491 (1,5,6,7-tetrahydro-2-(4-pyridinyl)-4H-pyrrolo[3,2-c]pyridin-4-one hydrochloride), a potent CK1 inhibitor of Arabidopsis, and found that PHA767491 analogues bearing a propargyl group at the pyrrole nitrogen atom (AMI-212) or a bromine atom at the pyrrole C3 position (AMI-23) enhance the period-lengthening activity. The period lengthening activity of a hybrid molecule of AMI-212 and AMI-23 (AMI-331) is about 100-fold stronger than that of PHA767491. An in vitro assay indicated a strong inhibitory activity of CK1 kinase by AMI-331. Also, affinity proteomics using an AMI-331 probe showed that targets of AMI-331 are mostly CK1 proteins. As such, AMI-331 is a strong potent CK1 inhibitor that shows promise in the research of CK1 in plants.

scholarly journals Casein Kinase 1D Encodes a Novel Drug Target in Hedgehog—GLI-Driven Cancers and Tumor-Initiating Cells Resistant to SMO Inhibition

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4227
Author(s):  
Elisabeth Peer ◽  
Sophie Karoline Aichberger ◽  
Filip Vilotic ◽  
Wolfgang Gruber ◽  
Thomas Parigger ◽  
...  
Keyword(s):  
Critical Role ◽  
Treatment Strategies ◽  
Casein Kinase ◽  
Tumor Initiating Cells ◽  
Casein Kinase 1 ◽  
Hh Signaling ◽  
Novel Drug ◽  
Smo Inhibitor

(1) Background: Aberrant activation of the hedgehog (HH)—GLI pathway in stem-like tumor-initiating cells (TIC) is a frequent oncogenic driver signal in various human malignancies. Remarkable efficacy of anti-HH therapeutics led to the approval of HH inhibitors targeting the key pathway effector smoothened (SMO) in basal cell carcinoma and acute myeloid leukemia. However, frequent development of drug resistance and severe adverse effects of SMO inhibitors pose major challenges that require alternative treatment strategies targeting HH—GLI in TIC downstream of SMO. We therefore investigated members of the casein kinase 1 (CSNK1) family as novel drug targets in HH—GLI-driven malignancies. (2) Methods: We genetically and pharmacologically inhibited CSNK1D in HH-dependent cancer cells displaying either sensitivity or resistance to SMO inhibitors. To address the role of CSNK1D in oncogenic HH signaling and tumor growth and initiation, we quantitatively analyzed HH target gene expression, performed genetic and chemical perturbations of CSNK1D activity, and monitored the oncogenic transformation of TIC in vitro and in vivo using 3D clonogenic tumor spheroid assays and xenograft models. (3) Results: We show that CSNK1D plays a critical role in controlling oncogenic GLI activity downstream of SMO. We provide evidence that inhibition of CSNK1D interferes with oncogenic HH signaling in both SMO inhibitor-sensitive and -resistant tumor settings. Furthermore, genetic and pharmacologic perturbation of CSNK1D decreases the clonogenic growth of GLI-dependent TIC in vitro and in vivo. (4) Conclusions: Pharmacologic targeting of CSNK1D represents a novel therapeutic approach for the treatment of both SMO inhibitor-sensitive and -resistant tumors.

scholarly journals Casein kinase 1D encodes a novel drug target in Hedgehog-GLI driven cancers and tumor-initiating cells resistant to SMO inhibition

2021 ◽  
Author(s):  
Elisabeth Peer ◽  
Sophie K Aichberger ◽  
Filip Vilotic ◽  
Gruber Wolfgang ◽  
Thomas Parigger ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Critical Role ◽  
Casein Kinase ◽  
Tumor Initiating Cells ◽  
Casein Kinase 1 ◽  
Hh Signaling ◽  
Novel Drug ◽  
Smo Inhibitor

Abstract: (1) Background: Aberrant activation of the Hedgehog (HH)/GLI pathway in stem-like tumor initiating cells (TIC) is a frequent oncogenic driver signal in various human malignancies. Remarkable efficacy of anti-HH therapeutics led to the approval of HH inhibitors targeting the key pathway effector Smoothened (SMO) in basal cell carcinoma and acute myeloid leukemia. However, frequent development of drug resistance and severe adverse effects of SMO inhibitors pose major challenges that require alternative treatment strategies targeting HH/GLI in TIC downstream of SMO. We therefore investigated members of the casein kinase 1 (CSNK1) family as novel drug targets in HH/GLI driven malignancies. (2) Methods: We genetically and pharmacologically inhibited CSNK1D in HH-dependent cancer cells displaying either sensitivity or resistance to SMO inhibitors. To address the role of CSNK1D in oncogenic HH signaling and tumor growth and initiation, we quantitatively analyzed HH target gene expression, performed genetic and chemical perturbations of CSNK1D activity and monitored oncogenic transformation of TIC in vitro and in vivo using 3D clonogenic tumor spheroid assays and xenograft models. (3) Results: We show that CSNK1D plays a critical role in controlling oncogenic GLI activity downstream of SMO. We provide evidence that inhibition of CSNK1D interferes with oncogenic HH signaling in both SMO-inhibitor sensitive and resistant tumor settings. Furthermore, genetic and pharmacologic perturbation of CSNK1D decreases the clonogenic growth of GLI-dependent tumor-initiating cancer cells in vitro and in vivo. (4) Conclusions: Pharmacologic targeting of CSNK1D represents a novel therapeutic approach for the treatment of both SMO inhibitor sensitive and resistant tumors.

scholarly journals Identification of Domains Responsible for Ubiquitin-Dependent Degradation of dMyc by Glycogen Synthase Kinase 3β and Casein Kinase 1 Kinases

2009 ◽  
Vol 29 (12) ◽  
pp. 3424-3434 ◽  
Author(s):  
Margherita Galletti ◽  
Sara Riccardo ◽  
Federica Parisi ◽  
Carlina Lora ◽  
Mahesh Kumar Saqcena ◽  
...  
Keyword(s):  
Compound Eye ◽  
Glycogen Synthase ◽  
Physiological Role ◽  
Casein Kinase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Casein Kinase 1 ◽  
The One

ABSTRACT In the present study, we report that ubiquitin-mediated degradation of dMyc, the Drosophila homologue of the human c-myc proto-oncogene, is regulated in vitro and in vivo by members of the casein kinase 1 (CK1) family and by glycogen synthase kinase 3β (GSK3β). Using Drosophila S2 cells, we demonstrate that CK1α promotes dMyc ubiquitination and degradation with a mechanism similar to the one mediated by GSK3β in vertebrates. Mutation of ck1α or -ε or sgg/gsk3β in Drosophila wing imaginal discs results in the accumulation of dMyc protein, suggesting a physiological role for these kinases in vivo. Analysis of the dMyc amino acid sequence reveals the presence of conserved domains containing potential phosphorylation sites for mitogen kinases, GSK3β, and members of the CK1 family. We demonstrate that mutations of specific residues within these phosphorylation domains regulate dMyc protein stability and confer resistance to degradation by CK1α and GSK3β kinases. Expression of the dMyc mutants in the compound eye of the adult fly results in a visible defect that is attributed to the effect of dMyc on growth, cell death, and inhibition of ommatidial differentiation.

scholarly journals Casein kinase-1γ1 and 3 stimulate tumor necrosis factor-induced necroptosis through RIPK3

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Song-Yi Lee ◽  
Hyunjoo Kim ◽  
Cathena Meiling Li ◽  
Jaemin Kang ◽  
Ayaz Najafov ◽  
...  
Keyword(s):  
Ectopic Expression ◽  
Specific Inhibitor ◽  
Casein Kinase ◽  
In Vitro Assays ◽  
Serine Threonine Kinase ◽  
Casein Kinase 1 ◽  
Threonine Kinase ◽  
Necrosis Factor

AbstractUpon necroptosis activation, receptor interacting serine/threonine kinase (RIPK)1 and RIPK3 form a necrosome complex with pseudokinase mixed lineage kinase-like (MLKL). Although protein phosphorylation is a key event for RIPK1 and RIPK3 activation in response to a necroptosis signal, relatively little is known about other factors that might regulate the activity of these kinases or necrosome formation. Through a gain-of-function screen with 546 kinases and 127 phosphatases, we identified casein kinase 1 gamma (CK1γ) as a candidate necroptosis-promoting factor. Here, we show that the decreased activity or amounts of CK1γ1 and CK1γ3, either by treatment with a chemical inhibitor or knockdown in cells, reduced TNFα-induced necroptosis. Conversely, ectopic expression of CK1γ1 or CK1γ3 exacerbated necroptosis, but not apoptosis. Similar to RIPK1 and RIPK3, CK1γ1 was also cleaved at Asp343 by caspase-8 during apoptosis. CK1γ1 and CK1γ3 formed a protein complex and were recruited to the necrosome harboring RIPK1, RIPK3 and MLKL. In particular, an autophosphorylated form of CK1γ3 at Ser344/345 was detected in the necrosome and was required to mediate the necroptosis. In addition, in vitro assays with purified proteins showed that CK1γ phosphorylated RIPK3, affecting its activity, and in vivo assays showed that the CK1γ-specific inhibitor Gi prevented abrupt death in mice with hypothermia in a model of TNFα-induced systemic inflammatory response syndrome. Collectively, these data suggest that CK1γ1 and CK1γ3 are required for TNFα-induced necroptosis likely by regulating RIPK3.

scholarly journals T. cruzi DNA polymerase beta (Tcpolβ) is phosphorylated in vitro by CK1, CK2 and TcAUK1 leading to the potentiation of its DNA synthesis activity

2021 ◽  
Vol 15 (7) ◽  
pp. e0009588
Author(s):  
Edio Maldonado ◽  
Diego A. Rojas ◽  
Fabiola Urbina ◽  
Aldo Solari
Keyword(s):  
Protein Kinases ◽  
Dna Polymerase ◽  
Excision Repair ◽  
Polymerase Activity ◽  
Casein Kinase ◽  
Phosphorylation Sites ◽  
Casein Kinase 1 ◽  
Synthesis Activity

The unicellular protozoan Trypanosoma cruzi is the causing agent of Chagas disease which affects several millions of people around the world. The components of the cell signaling pathways in this parasite have not been well studied yet, although its genome can encode several components able to transduce the signals, such as protein kinases and phosphatases. In a previous work we have found that DNA polymerase β (Tcpolβ) can be phosphorylated in vivo and this modification activates the synthesis activity of the enzyme. Tcpolβ is kinetoplast-located and is a key enzyme in the DNA base excision repair (BER) system. The polypeptide possesses several consensus phosphorylation sites for several protein kinases, however, a direct phosphorylation of those sites by specific kinases has not been reported yet. Tcpolβ has consensus phosphorylation sites for casein kinase 1 (CK1), casein kinase 2 (CK2) and aurora kinase (AUK). Genes encoding orthologues of those kinases exist in T. cruzi and we were able to identify the genes and to express them to investigate whether or no Tcpolβ could be a substrate for in vitro phosphorylation by those kinases. Both CK1 and TcAUK1 have auto-phosphorylation activities and they are able to phosphorylate Tcpolβ. CK2 cannot perform auto-phosphorylation of its subunits, however, it was able to phosphorylate Tcpolβ. Pharmacological inhibitors used to inhibit the homologous mammalian kinases can also inhibit the activity of T. cruzi kinases, although, at higher concentrations. The phosphorylation events carried out by those kinases can potentiate the DNA polymerase activity of Tcpolβ and it is discussed the role of the phosphorylation on the DNA polymerase and lyase activities of Tcpolβ. Taken altogether, indicates that CK1, CK2 and TcAUK1 can play an in vivo role regulating the function of Tcpolβ.

scholarly journals Three Kinetically Distinct Ca2+-Independent Depolarization-Activated K+ Currents in Callosal-Projecting Rat Visual Cortical Neurons

1997 ◽  
Vol 78 (5) ◽  
pp. 2309-2320 ◽  
Author(s):  
Rachel E. Locke ◽  
Jeanne M. Nerbonne
Keyword(s):  
Steady State ◽  
Cortical Neurons ◽  
Differential Sensitivity ◽  
Kinetic Properties ◽  
Time Constants ◽  
Steady State Inactivation ◽  
Order Of Magnitude ◽  
Visual Cortical

Locke, Rachel E. and Jeanne M. Nerbonne. Three kinetically distinct Ca2+-independent depolarization-activated K+ currents in callosal-projecting rat visual cortical neurons. J. Neurophysiol. 78: 2309–2320, 1997. Whole cell, Ca2+-independent, depolarization-activated K+ currents were characterized in identified callosal-projecting (CP) neurons isolated from postnatal day 7–16 rat primary visual cortex. CP neurons were identified in vitro after in vivo retrograde labeling with fluorescently tagged latex microbeads. During brief (160-ms) depolarizing voltage steps to potentials between −50 and +60 mV, outward K+ currents in these cells activate rapidly and inactivate to varying degrees. Three distinct K+ currents were separated based on differential sensitivity to 4-aminopyridine (4-AP); these are referred to here as I A, I D, and I K, because their properties are similar (but not identical) K+ currents termed I A, I D, and I K in other cells. The current sensitive to high (≥100 μM) concentrations of 4-AP ( I A) activates and inactivates rapidly; the current blocked completely by low (≤50 μM) 4-AP ( I D) activates rapidly and inactivates slowly. A slowly activating, slowly inactivating current ( I K) remains in the presence of 5 mM 4-AP. I A, I D, and I K also were separated and characterized in experiments that did not rely on the use of 4-AP. All CP cells express all three K+ current types, although the relative densities of I A, I D, and I K vary among cells. The experiments here also have revealed that I A, I D, and I K display similar voltage dependences of activation and steady state inactivation, whereas the kinetic properties of the currents are distinct. At +30 mV, for example, mean ± SD activation τs are 0.83 ± 0.24 ms for I A, 1.74 ± 0.49 ms for I D, and 14.7 ± 4.0 ms for I K. Mean ± SD inactivation τs for I A and I D are 26 ± 7 ms and 569 ± 143 ms, respectively. Inactivation of I K is biexponential with mean ± SD inactivation time constants of 475 ± 232 ms and 3,128 ± 1,328 ms; ∼20% of the 4-AP–insensitive current is noninactivating. For all three components, activation is voltage dependent, increasing with increasing depolarization, whereas inactivation is voltage independent. Both I A and I K recover rapidly from steady state inactivation with mean ± SD recovery time constants of 38 ± 7 ms and 79 ± 26 ms, respectively; I D recovers an order of magnitude more slowly (588 ± 274 ms). The properties of I A, I D, and I K in CP neurons are compared with those of similar currents described previously in other mammalian central neurons and, in the accompanying paper, the roles of these conductances in regulating the firing properties of CP neurons are explored.

scholarly journals p53 is phosphorylated in vitro and in vivo by the delta and epsilon isoforms of casein kinase 1 and enhances the level of casein kinase 1 delta in response to topoisomerase-directed drugs

Oncogene ◽  
1997 ◽  
Vol 15 (14) ◽  
pp. 1727-1736 ◽  
Author(s):  
U Knippschild ◽  
D M Milne ◽  
L E Campbell ◽  
A J DeMaggio ◽  
E Christenson ◽  
...  
Keyword(s):  
Casein Kinase ◽  
Casein Kinase 1

scholarly journals Host casein kinase 1-mediated phosphorylation modulates phase separation of a rhabdovirus phosphoprotein and virus infection

2021 ◽  
Author(s):  
Xiao-Dong Fang ◽  
Qiang Gao ◽  
Ying Zang ◽  
Ji-Hui Qiao ◽  
Dong-Min Gao ◽  
...  
Keyword(s):  
Phase Separation ◽  
Virus Infection ◽  
Casein Kinase ◽  
Casein Kinase 1 ◽  
N Protein ◽  
Intrinsically Disordered ◽  
P Protein ◽  
L Proteins

Liquid–liquid phase separation (LLPS) plays important roles in forming cellular membraneless organelles. However, how host factors regulate LLPS of viral proteins during negative-sense RNA (NSR) virus infections is largely unknown. Here, we used Barley yellow striate mosaic virus (BYSMV) as a model to demonstrate regulation of host casein kinase 1 in phase separation and infection of NSR viruses. We first found that the BYSMV phosphoprotein (P) formed spherical granules with liquid properties and recruited viral nucleotide (N) and polymerase (L) proteins in vivo. Moreover, the P-formed granules were tethered to the ER/actin network for trafficking and fusion. BYSMV P alone formed droplets and incorporated the N protein and genomic RNA in vitro. Interestingly, phase separation of BYSMV P was inhibited by host casein kinase 1 (CK1)-dependent phosphorylation of an intrinsically disordered P protein region. Genetic assays demonstrated that the unphosphorylated mutant of BYSMV P exhibited condensed phase, which promoted virus replication through concentrating the N, L proteins, and genome RNA into viroplasms. Whereas, the phosphorylation-mimic mutant existed in diffuse phase state leading to enhanced virus transcription. Collectively, our results demonstrate that host CK1 modulates phase separation of viral P protein and virus infection.

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