cAMP-dependent kinase does not modulate the Slack sodium-activated potassium channel

Nuwer, Megan O.; Picchione, Kelly E.; Bhattacharjee, Abhishek

doi:10.1016/j.neuropharm.2009.06.006

Cited by 17 publications

(16 citation statements)

References 28 publications

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“…In contrast to the effects of PKC on Slack channels that were described above, the effects of PKA on Slack are indirect and do not involve phosphorylation of the channel subunit itself [23, 65]. Slack channels in HEK-293 cells are insensitive to cyclic AMP analogs or to the PKA inhibitor KT5720, and application of the catalytic subunit of PKA to the cytoplasmic face of Slack channels excised from transfected cells or dorsal root ganglion neurons has no effect on channel opening.…”

Section: Cellular Regulation Of Kna Channelsmentioning

confidence: 99%

Slack, Slick, and Sodium-Activated Potassium Channels

2013

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The Slack and Slick genes encode potassium channels that are very widely expressed in the central nervous system. These channels are activated by elevations in intracellular sodium, such as those that occur during trains of one or more action potentials, or following activation of nonselective cationic neurotransmitter receptors such as AMPA receptors. This review covers the cellular and molecular properties of Slack and Slick channels and compares them with findings on the properties of sodium-activated potassium currents (termed KNa currents) in native neurons. Human mutations in Slack channels produce extremely severe defects in learning and development, suggesting that KNa channels play a central role in neuronal plasticity and intellectual function.

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Section: Cellular Regulation Of Kna Channelsmentioning

confidence: 99%

Slack, Slick, and Sodium-Activated Potassium Channels

2013

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“…It was suggested that K Na channels in DRG contribute to AP accommodation due to their increasing activation by Na + influx through the voltage-gated sodium channels during AP firing. It was further hypothesized that PKA-induced internalisation of Slo2.2 channels in DRG neurons contributes to the increased excitability and loss of firing accommodation in hyperalgesia [82]. …”

Section: Other K+ Channelsmentioning

confidence: 99%

Potassium Channels in Peripheral Pain Pathways: Expression, Function and Therapeutic Potential

Du¹,

Gamper²

2013

114

103

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Electrical excitation of peripheral somatosensory nerves is a first step in generation of most pain signals in mammalian nervous system. Such excitation is controlled by an intricate set of ion channels that are coordinated to produce a degree of excitation that is proportional to the strength of the external stimulation. However, in many disease states this coordination is disrupted resulting in deregulated peripheral excitability which, in turn, may underpin pathological pain states (i.e. migraine, neuralgia, neuropathic and inflammatory pains). One of the major groups of ion channels that are essential for controlling neuronal excitability is potassium channel family and, hereby, the focus of this review is on the K+ channels in peripheral pain pathways. The aim of the review is threefold. First, we will discuss current evidence for the expression and functional role of various K+ channels in peripheral nociceptive fibres. Second, we will consider a hypothesis suggesting that reduced functional activity of K+ channels within peripheral nociceptive pathways is a general feature of many types of pain. Third, we will evaluate the perspectives of pharmacological enhancement of K+ channels in nociceptive pathways as a strategy for new analgesic drug design.

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“…Our group has recently shown that PKA does not directly affect Slack channels when expressed in HEK-293 cells (Nuwer et al, 2009). Still based on the observed inhibition of K Na by PKA described above, we sought to determine whether the gating of native K Na channels recorded from DRG neurons exhibited PKA sensitivity.…”

Section: K Na Channel Gating Is Not Affected By Pka Modulationmentioning

confidence: 99%

“…We first investigated the membrane expression of Slack before and after PKA activation by labeling the N-terminal of the Slack protein with emerald green fluorescent protein (NtermGFP-Slack). We tagged the N-terminal instead of the C-terminal because the C-terminal portion of the protein contains all of the PKA consensus sites (Joiner et al, 1998;Nuwer et al, 2009) and a PDZ binding motif (Joiner et al, 1998). The NtermGFP-Slack produced Slack-like currents when expressed in HEK-293 cells (supplemental Fig.…”

Section: K Na Channel Gating Is Not Affected By Pka Modulationmentioning

confidence: 99%

“…Both channel subunits contain large C termini consisting of tandem RCK domains (regulators of K ϩ conductance) (Jiang et al, 2002;Ye et al, 2006) with many consensus PKA and protein kinase C (PKC) phosphorylation sites (Joiner et al, 1998;Bhattacharjee et al, 2003). Although sensitive to PKC regulation (Santi et al, 2006), recombinant Slack channels are unresponsive to PKA modulation (Nuwer et al, 2009). Most of the PKA consensus in Slack are located outside the RCK domains, suggesting that PKA modulation of Slack K Na channels should not affect gating but could involve protein-protein interaction and consequently trafficking of channels.…”

Section: Introductionmentioning

confidence: 99%

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PKA-Induced Internalization of Slack K_NaChannels Produces Dorsal Root Ganglion Neuron Hyperexcitability

Nuwer¹,

Picchione²,

Bhattacharjee³

2010

J. Neurosci.

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Inflammatory mediators through the activation of the protein kinase A (PKA) pathway sensitize primary afferent nociceptors to mechanical, thermal, and osmotic stimuli. However, it is unclear which ion conductances are responsible for PKA-induced nociceptor hyperexcitability. We have previously shown the abundant expression of Slack sodium-activated potassium (K Na ) channels in nociceptive dorsal root ganglion (DRG) neurons. Here we show using cultured DRG neurons, that of the total potassium current, I K , the K Na current is predominantly inhibited by PKA. We demonstrate that PKA modulation of K Na channels does not happen at the level of channel gating but arises from the internal trafficking of Slack channels from DRG membranes. Furthermore, we found that knocking down the Slack subunit by RNA interference causes a loss of firing accommodation analogous to that observed during PKA activation. Our data suggest that the change in nociceptive firing occurring during inflammation is the result of PKA-induced Slack channel trafficking.

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cAMP-dependent kinase does not modulate the Slack sodium-activated potassium channel

Cited by 17 publications

References 28 publications

Slack, Slick, and Sodium-Activated Potassium Channels

Slack, Slick, and Sodium-Activated Potassium Channels

Potassium Channels in Peripheral Pain Pathways: Expression, Function and Therapeutic Potential

PKA-Induced Internalization of Slack K_NaChannels Produces Dorsal Root Ganglion Neuron Hyperexcitability

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cAMP-dependent kinase does not modulate the Slack sodium-activated potassium channel

Cited by 17 publications

References 28 publications

Slack, Slick, and Sodium-Activated Potassium Channels

Slack, Slick, and Sodium-Activated Potassium Channels

Potassium Channels in Peripheral Pain Pathways: Expression, Function and Therapeutic Potential

PKA-Induced Internalization of Slack KNaChannels Produces Dorsal Root Ganglion Neuron Hyperexcitability

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PKA-Induced Internalization of Slack K_NaChannels Produces Dorsal Root Ganglion Neuron Hyperexcitability