Involvement of Dominant-negative Spliced Variants of the Intermediate Conductance Ca2+-activated K+ Channel, KCa3.1, in Immune Function of Lymphoid Cells

Ohya, Susumu; Niwa, Shin‐Ichi; Yanagi, Ayano; Fukuyo, Yuka; Yamamura, Hisao; Imaizumi, Yuji

doi:10.1074/jbc.m110.184192

Cited by 31 publications

(28 citation statements)

References 49 publications

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“…Notch2 splice variants may act in a dominant-negative manner that compromises the functions of Notch2-FL and are likely to block corresponding signaling pathways in AML cells. 7,[37][38][39] Based on these discoveries and the findings presented here, we suggest that silencing of the Notch2 signaling pathway could be a due to dominantnegative effects of Notch2 splice variants on Notch2-FL. It is thus possible to speculate that Notch2 pathway reactivation could be achieved by the using of blocking antibodies against Notch2-Va and Notch2-Vb splice variants.…”

Section: Discussionsupporting

confidence: 62%

NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

Adamia

Bar-Natan

Haibe‐Kains

et al. 2014

Blood

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• Overall, our results suggest that NOTCH2 and FLT3 aberrant splicing is a common event in AML that correlates with disease status and may correlate with disease outcomes. • Selected variants of NOTCH2and FLT3 transcripts were detected in a significant number of AML patients and could be useful as disease markers.Our previous studies revealed an increase in alternative splicing of multiple RNAs in cells from patients with acute myeloid leukemia (AML) compared with CD34 1 bone marrow cells from normal donors. Aberrantly spliced genes included a number of oncogenes, tumor suppressor genes, and genes involved in regulation of apoptosis, cell cycle, and cell differentiation. Among the most commonly mis-spliced genes (>70% of AML patients) were 2, NOTCH2 and FLT3, that encode myeloid cell surface proteins. The splice variants of NOTCH2 and FLT3 resulted from complete or partial exon skipping and utilization of cryptic splice sites. Longitudinal analyses suggested that NOTCH2 and FLT3 aberrant splicing correlated with disease status. Correlation analyses between splice variants of these genes and clinical features of patients showed an association between NOTCH2-Va splice variant and overall survival of patients. Our results suggest that NOTCH2 and FLT3 mis-splicing is a common characteristic of AML and has the potential to generate transcripts encoding proteins with altered function. Thus, splice variants of these genes might provide disease markers and targets for novel therapeutics. (Blood. 2014;123(18):2816-2825

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Section: Discussionsupporting

confidence: 62%

NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

Adamia

Bar-Natan

Haibe‐Kains

et al. 2014

Blood

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“…Possibly, in guinea pig DSM, IK channels are expressed in the cytoplasm but normally are not trafficking to the cell membrane. A recent study shows that the IK channel has two splice variants, one expressed in the plasma membrane and the other one in the cytoplasm, and further suggests that alternative splicing events are responsible for the fine-tuning of IK channel activity under physiological and pathophysiological conditions (Ohya et al, 2011). Indeed, a role for IK channels has been demonstrated in some vascular smooth muscle cells under pathological conditions (Tharp and Bowles, 2009).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Activation of Small Conductance Calcium-Activated Potassium Channels with Naphtho[1,2-d]thiazol-2-ylamine Decreases Guinea Pig Detrusor Smooth Muscle Excitability and Contractility

Parajuli

Soder

Hristov

et al. 2011

J Pharmacol Exp Ther

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Small conductance Ca 2ϩ -activated K ϩ (SK) and intermediate conductance Ca 2ϩ -activated K ϩ (IK) channels are thought to be involved in detrusor smooth muscle (DSM) excitability and contractility. Using naphtho[1,2-d]thiazol-2-ylamine (SKA-31), a novel and highly specific SK/IK channel activator, we investigated whether pharmacological activation of SK/IK channels reduced guinea pig DSM excitability and contractility. We detected the expression of all known isoforms of SK (SK1-SK3) and IK channels at mRNA and protein levels in DSM by singlecell reverse transcription-polymerase chain reaction and Western blot. Using the perforated patch-clamp technique on freshly isolated DSM cells, we observed that SKA-31 (10 M) increased SK currents, which were blocked by apamin (1 M), a selective SK channel inhibitor. In current-clamp mode, SKA-31 (10 M) hyperpolarized the cell resting membrane potential, which was blocked by apamin (1 M) but not by 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) (1 M), a selective IK channel inhibitor. SKA-31 (10 nM-10 M) significantly inhibited the spontaneous phasic contraction amplitude, frequency, duration, and muscle force in DSM isolated strips. The SKA-31 inhibitory effects on DSM contractility were blocked by apamin (1 M) but not by TRAM-34 (1 M), which did not per se significantly affect DSM spontaneous contractility. SK channel activation with SKA-31 reduced contractions evoked by electrical field stimulation. SKA-31 effects were reversible upon washout. In conclusion, SK channels, but not IK channels, mediate SKA-31 effects in guinea pig DSM. Pharmacological activation of SK channels reduces DSM excitability and contractility and therefore may provide a novel therapeutic approach for controlling bladder dysfunction.

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“…No difference in K Ca 3.1 mRNA expression was found between passages, but all experiments were performed between passages 4 and 5 for consistency Myofibroblasts express K Ca 3.1 protein K Ca 3.1 protein expression in human lung myofibroblasts was identified by Western blot (n=6 NFC, n=5 IPF). The predicted weight of K Ca 3.1 is 48kDa, but larger forms of ~53kDa and several shorter splice variants exist [11,[24][25][26]. Using two different anti-K Ca 3.1 antibodies, M20 and P4997, a consistent band of ~48kDa was observed (Figure 3a).…”

Section: Myofibroblasts Express K Ca 31 Channel Mrna Which Is Up-rementioning

confidence: 84%

The K+ Channel KCa3.1 As A Novel Target For Idiopathic Pulmonary Fibrosis

Roach¹,

Shepherd²,

Sabir³

et al. 2012

A61. Antifibrotics and Therapeutic Targets in Experimental Lung Fibrosis

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Involvement of Dominant-negative Spliced Variants of the Intermediate Conductance Ca2+-activated K+ Channel, KCa3.1, in Immune Function of Lymphoid Cells

Cited by 31 publications

References 49 publications

NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

Pharmacological Activation of Small Conductance Calcium-Activated Potassium Channels with Naphtho[1,2-d]thiazol-2-ylamine Decreases Guinea Pig Detrusor Smooth Muscle Excitability and Contractility

The K+ Channel KCa3.1 As A Novel Target For Idiopathic Pulmonary Fibrosis

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