Association of Src Tyrosine Kinase with a Human Potassium Channel Mediated by SH3 Domain

Holmes, Todd C.; Fadool, James M.; Ren, Ruibao; Levitan, Irwin B.

doi:10.1126/science.274.5295.2089

Cited by 246 publications

(230 citation statements)

References 28 publications

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“…For example, genistein has been shown to inhibit I to in rat ventricular [27] and human atrial [44] myocytes. In expressed Shaker channels (Kv1.5, Kv1.4), Src tyrosine kinase binds to the α-subunit and inhibits macroscopic currents [45,46], although rat Kv1.5 does not co-immunoprecipitate with Src as does the human isoform [46]. Finally, inhibition of specific tyrosine phosphatases has been shown to increase currents carried by Kv2.1 channels [47].…”

Section: Differential Control Of K + Currents By Thioredoxin and Glutmentioning

confidence: 99%

Oxidoreductase regulation of Kv currents in rat ventricle

Liang

et al. 2008

Journal of Molecular and Cellular Cardiology

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Oxidative stress contributes to the arrhythmogenic substrate created by myocardial ischemiareperfusion partly through a shift in cell redox state, a key modulator of protein function. The activity of many oxidation-sensitive proteins is controlled by oxidoreductase systems that regulate the redox state of cysteine thiol groups, but the impact of these systems on ion channel function is not well defined. Thus, we examined the roles of the thioredoxin and glutaredoxin systems in controlling K + channels in the ventricle. An oxidative shift in redox state was elicited in isolated rat ventricular myocytes by brief exposure to diamide, a thiol-specific, membrane-permeable oxidant. Voltageclamp studies showed that diamide decreased peak outward K + current (I peak ) evoked by depolarizing test pulses by 41% (+60 mV; p<0.05) while steady-state outward current (I ss ) measured at the end of the test pulse was decreased by 45% (p<0.05). These electrophysiological effects were not prevented by protein kinase C blockers, but the tyrosine kinase inhibitors genistein or lavendustin A blocked the suppression of both K + currents by diamide. Moreover, inhibition of I peak and I ss by diamide was reversed by dichloroacetate and an insulin-mimetic. The effect of dichloroacetate to normalize I peak after diamide was blocked by the thioredoxin system inhibitors auranofin or 13-cisretinoic acid, but I ss was not affected by either compound. A pan-specific inhibitor of glutaredoxin and thioredoxin systems, 1,3-bis-(2-chloroethyl)-1-nitrosourea, also blocked the dichloroacetate effect on I peak but only partially inhibited the recovery of I ss . These data suggest that acute regulation of cardiac K + channels by oxidoreductase systems is mediated by redox-sensitive tyrosine kinase/ phosphatase pathways. The pathways controlling I peak channels are targets of the thioredoxin system whereas those regulating I ss channels are likely controlled by the glutaredoxin system. Thus, cardiac oxidoreductase systems may be important regulators of ion channels affected by pathogenic oxidative stress.

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Section: Differential Control Of K + Currents By Thioredoxin and Glutmentioning

confidence: 99%

Oxidoreductase regulation of Kv currents in rat ventricle

Liang

et al. 2008

Journal of Molecular and Cellular Cardiology

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“…The effect of fast loss of intracellular K + on caspase activation suggests that there is a crosstalk occurring between activation of the K + channel and intracellular signaling pathways. There is accumulating evidence that support the existence of such a crosstalk, including: (1) voltage-gated K + channel activity involved in cell proliferation (Lu et al, 1993;Xu et al, 1996); (2) Kv channel activity regulated by growth factors (Xu et al, 1999;Roderick et al, 2003); and (3) Kv channel activity associated with Src tyrosine kinase (Holmes et al, 1996;Nitabach et al, 2001). More importantly, portions of the MAP kinase signaling pathways, including JNK/SAPK and p38 signaling pathways, mediate UV irradiation-induced corneal epithelial cell apoptosis (Adler et al, 1996;Price et al, 1996;Merienne et al, 2000;Bodero et al, 2003;Lu et al, 2003).…”

Section: Uv-induced K + Channel and Jnk Activationmentioning

confidence: 99%

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

2006

Progress in Retinal and Eye Research

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One of the functional roles of the corneal epithelial layer is to protect the cornea, lens and other underlying ocular structures from damages caused by environmental insults. It is important for corneal epithelial cells to maintain this function by undergoing continuous renewal through a dynamic process of wound healing. Previous studies in corneal epithelial cells have provided substantial evidence showing that environmental insults, such as ultraviolet (UV) irradiation and other biohazards, can induce stress-related cellular responses resulting in apoptosis and thus interrupt the dynamic process of wound healing. We found that UV irradiation-induced apoptotic effects in corneal epithelial cells are started by the hyperactivation of K + channels in the cell membrane resulting in a fast loss of intracellular K + ions. Recent studies provide further evidence indicating that these complex responses in corneal epithelial cells are resulted from the activation of stressrelated signaling pathways mediated by K + channel activity. The effect of UV irradiation on corneal epithelial cell fate shares common signaling mechanisms involving the activation of intracellular responses that are often activated by the stimulation of various cytokines. One piece of evidence for making this distinction is that at early times UV irradiation activates a Kv3.4 channel in corneal epithelial cells to elicit activation of c-Jun N-terminal kinase cascades and p53 activation leading to cell cycle arrest and apoptosis. The hypothetic model is that UV-induced potassium channel hyperactivity as an early event initiates fast cell shrinkages due to the loss of intracellular potassium, resulting in the activation of scaffolding protein kinases and cytoskeleton reorganizations. This review article presents important control mechanisms that determine Kv channel activity-mediated cellular responses in corneal epithelial cells, involving activation of stress-induced signaling pathways, arrests of cell cycle progression and/or induction of apoptosis.

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“…However, they may just add to an ever growing list of molecules that Src is able to phosphorylate. For example, it is clear that a number of receptors and channels can be phosphorylated by Src family members and that this phosphorylation can lead to altered activity (Holmes et al, 1996;Yu et al, 1997). The role and importance of phosphorylation by Src will need to be determined in each individual pathway.…”

Section: Kinase Domainmentioning

confidence: 99%

“…How these nuclear interactions relate to other signaling pathways remains unclear. One further pathway that is regulated by SH3 inte-ractions is the regulation of the potassium channel ± interactions with this channel have been shown to be mediated by the Src SH3 domain (Holmes et al, 1996).…”

Section: Role Of the Sh3 And Sh2 Protein Interaction Domainsmentioning

confidence: 99%