Elimination of rapid potassium channel inactivation by phosphorylation of the inactivation gate

Covarrubias, Manuel; Wei, Aguan; Salkoff, Lawrence; Vyas, T. B.

doi:10.1016/0896-6273(94)90425-1

Cited by 142 publications

(129 citation statements)

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“…[12][13][14] Early reports showed modulation of fast Kv3.4 channel inactivation by oxidation, phosphorylation and PIP2 in heterologous expression systems. [15][16][17][18] Demonstrating that inactivation modulation also occurs in neurons, we showed that PKC activation dramatically slows inactivation of the native Kv3.4 channel expressed in DRG nociceptors. 7 Under physiological conditions, however, Kv3.4 channel inactivation is not modulated by PIP2.…”

Section: Introductionmentioning

confidence: 95%

“…This is potentially significant because, in addition to phosphorylation, oxidation also eliminates Kv3.4 Ntype inactivation. 16,17 If the neuron is dialyzed with an oxidizing or PKC activating intracellular solution in the whole-cell configuration, Kv3.4 channels might switch from A-type to delayed rectifiertype. Further experimentation is, however, necessary to support this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

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Kv3.4 channel function and dysfunction in nociceptors

et al. 2015

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Section: Introductionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Kv3.4 channel function and dysfunction in nociceptors

et al. 2015

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“…Tyrosine kinase activation by G protein-coupled receptors (19) also suppresses delayed rectifying potassium channels by phosphorylation of a tyrosine residue in the amino terminus of Kv1.2 (20). Similarly, phosphorylation of serine residues in the amino terminus of a different delayed rectifying potassium channel Kv3.4 causes channel inactivation (21). Additionally, tyrosine phosphorylation of other potassium channels may regulate neuronal excitability.…”

mentioning

confidence: 99%

TrkB Activation by Brain-derived Neurotrophic Factor Inhibits the G Protein-gated Inward Rectifier Kir3 by Tyrosine Phosphorylation of the Channel

Rogalski

Appleyard

Pattillo

et al. 2000

Journal of Biological Chemistry

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G protein-activated inwardly rectifying potassium channels (Kir3) are widely expressed throughout the brain, and regulation of their activity modifies neuronal excitability and synaptic transmission. In this study, we show that the neurotrophin brain-derived neurotrophic factor (BDNF), through activation of TrkB receptors, strongly inhibited the basal activity of Kir3. This inhibition was subunit dependent as functional homomeric channels of either Kir3.1 or Kir3.4 were significantly inhibited, whereas homomeric channels composed of Kir3.2 were insensitive. The general tyrosine kinase inhibitors genistein, Gö 6976, and K252a but not the serine/threonine kinase inhibitor staurosporine blocked the BDNF-induced inhibition of the channel. BDNF was also found to directly stimulate channel phosphorylation because Kir3.1 immunoprecipitated from BDNFstimulated cells showed enhanced labeling by anti-phosphotyrosine-specific antibodies. The BDNF effect required specific tyrosine residues in the amino terminus of Kir3.1 and Kir3.4 channels. Mutations of either Tyr-12, Tyr-67, or both in Kir3.1 or mutation of either Tyr-32, Tyr-53, or both of Kir3.4 channels to phenylalanine significantly blocked the BDNF-induced inhibition. The insensitive Kir3.2 was made sensitive to BDNF by adding a tyrosine (D41Y) and a lysine (P32K) upstream to generate a phosphorylation site motif analogous to that present in Kir3.4. These results suggest that neurotrophin activation of TrkB receptors may physiologically control neuronal excitability by direct tyrosine phosphorylation of the Kir3.1 and Kir3.4 subunits of G protein-gated inwardly rectifying potassium channels.Neurotrophins are a family of growth factors that include nerve growth factor, BDNF, 1 NT3, and NT-4/5 (1) and activate receptor tyrosine kinases (Trk) to regulate neuronal survival and differentiation during brain development (2). Neurotrophins also rapidly modulate neuronal excitability to regulate synaptic plasticity in the hippocampus (3-7), plasticity of spinal cord neurons in models of chronic pain (8), and excitability of cortical neurons (9). The mechanisms of these neuronal effects on excitability are not yet known; however, BDNF was shown to rapidly modulate sodium channels in the CA1 region of the hippocampus (3) and to enhance synaptic currents in hippocampal postsynaptic neurons (6). These studies suggest that BDNF has direct effects on ion channel properties to modulate synaptic activity.The neurotrophin receptors are transmembrane tyrosine kinases, and BDNF activation of the TrkB receptor is known to initiate a cascade of phosphorylation events that activate a complex of signaling proteins (10). Tyrosine kinases directly phosphorylate ion channels to provide rapid regulation of neuronal excitability (11-18). Tyrosine kinase activation by G protein-coupled receptors (19) also suppresses delayed rectifying potassium channels by phosphorylation of a tyrosine residue in the amino terminus of Kv1.2 (20). Similarly, phosphorylation of serine residues in the amino terminus...

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“…Other Shaker-related K V channels, e.g., Shaker itself, K V 1.4, and K V 3.4, express outward currents that rapidly inactivate within milliseconds because of the presence of an amino-terminal inactivation domain (Hoshi et al, 1990). It was shown that phosphorylation of the amino-terminal inactivation domain of K V 3.4 channels by protein kinase C (PKC) completely eliminated N-type inactivation (Covarrubias et al, 1994). Also, dephosphorylation of a modulatory C-terminal site of Drosophila Shaker channels considerably slowed the inactivation rate (Drain et al, 1994).…”

mentioning

confidence: 99%

“…Covarrubias et al (1994) showed for the cloned human A-type K V channel, hK V 3.4 that PKC-dependent phosphorylation within the inactivation domain completely eliminates N-terminal inactivation. Conversely, Drain et al (1994) demonstrated for Shaker K V channels that the phosphorylation of a C-terminal consensus site by PKA induces an acceleration of the macroscopic and microscopic transition from the open channel into the inactivated state.…”

mentioning

confidence: 99%

Frequency-Dependent Inactivation of Mammalian A-Type K⁺Channel K_V1.4 Regulated by Ca²⁺/Calmodulin-Dependent Protein Kinase

Roeper¹,

Lorra²,

Pongs³

1997

J. Neurosci.

144

145

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Ca2ϩ /calmodulin dependent protein kinase (CaMKII) and protein phosphatase 2B (calcineurin) are key enzymes in the regulation of synaptic strength, controlling the phosphorylation status of pre-and postsynaptic target proteins. Here, we show that the inactivation gating of the Shaker-related fastinactivating K V channel, K v 1.4 is controlled by CaMKII and the calcineurin/inhibitor-1 protein phosphatase cascade. CaMKII phosphorylation of an amino-terminal residue of K V 1.4 leads to slowing of inactivation gating and accelerated recovery from N-type inactivated states. In contrast, dephosphorylation of this residue induces a fast inactivating mode of K V 1.4 with time constants of inactivation 5 to 10 times faster compared with the CaMKII-phosphorylated form. Dephosphorylated K V 1.4 channels also display slowed and partial recovery from inactivation with increased trapping of K V 1.4 channels in long-absorbing C-type inactivated states. In consequence, dephosphorylated K V 1.4 displays a markedly increased tendency to undergo cumulative inactivation during repetitive stimulation. The balance between phosphorylated and dephosphorylated K V 1.4 channels is regulated by changes in intracellular Ca 2ϩ concentration rendering K V 1.4 inactivation gating Ca 2ϩ -sensitive. The reciprocal CaMKII and calcineurin regulation of cumulative inactivation of presynaptic K V 1.4 may provide a novel mechanism to regulate the critical frequency for presynaptic spike broadening and induction of synaptic plasticity. Key words: voltage-activated K channels; Shaker; N-type inactivation; C-type inactivation; phosphorylation; CaMKII; calcineurin; protein phosphatase; synapseThe strength of synaptic connections within neuronal circuits is flexible. This plasticity in neuronal excitability has been recognized as an important property underlying short-and long-term changes in the concerted activity of pre-and postsynaptic elements including ion channels (Kandel et al., 1991;Bliss and Collingridge, 1993;Zucker, 1993). It has been shown for a number of ligand-and voltage-gated ion channels that their activity can be modulated by the activation of protein kinases and phosphatases, which are regulated, in turn, by second messenger systems, e.g., Ca 2ϩ and cAMP (Schulman, 1995). Potassium channels that constitute an extremely diverse superfamily involved in the control of pre-and postsynaptic excitability in this respect are particularly interesting. The regulation of potassium channel activity by protein phosphorylation may alter very distinctly neuronal excitability (Jonas and Kaszmarek, 1996).Several recent in vitro studies have focused on the Shaker superfamily of voltage-activated potassium (K V ) channels (Chandy and Gutman, 1994). It was shown that phosphorylation by protein tyrosine kinase reduced the activity of K V 1.2 and K V 1.3 channels (Huang et al., 1993;Lev et al., 1995;Holmes et al., 1996). Also, cAMP-dependent protein kinase A (PKA) phosphorylation upregulates the activity levels of K v 1.2 (Huang et al., 1994) and K V 2.1 (...

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Elimination of rapid potassium channel inactivation by phosphorylation of the inactivation gate

Cited by 142 publications

References 52 publications

Kv3.4 channel function and dysfunction in nociceptors

Kv3.4 channel function and dysfunction in nociceptors

TrkB Activation by Brain-derived Neurotrophic Factor Inhibits the G Protein-gated Inward Rectifier Kir3 by Tyrosine Phosphorylation of the Channel

Frequency-Dependent Inactivation of Mammalian A-Type K⁺Channel K_V1.4 Regulated by Ca²⁺/Calmodulin-Dependent Protein Kinase

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Elimination of rapid potassium channel inactivation by phosphorylation of the inactivation gate

Cited by 142 publications

References 52 publications

Kv3.4 channel function and dysfunction in nociceptors

Kv3.4 channel function and dysfunction in nociceptors

TrkB Activation by Brain-derived Neurotrophic Factor Inhibits the G Protein-gated Inward Rectifier Kir3 by Tyrosine Phosphorylation of the Channel

Frequency-Dependent Inactivation of Mammalian A-Type K+Channel KV1.4 Regulated by Ca2+/Calmodulin-Dependent Protein Kinase

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Frequency-Dependent Inactivation of Mammalian A-Type K⁺Channel K_V1.4 Regulated by Ca²⁺/Calmodulin-Dependent Protein Kinase