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Schrader LA, Ren Y, Cheng F, Bui D, Sweatt JD, Anderson AE.
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Transient outward K+ currents are particularly important for the regulation of membrane excitability of neurons and repolarization of action potentials in cardiac myocytes. These currents are modulated by PKC (protein kinase C) activation, and the K+- channel subunit Kv4.2 is a major contributor to these currents. Furthermore, the current recorded from Kv4.2 channels expressed in oocytes is reduced by PKC activation. The mechanism underlying PKC regulation of Kv4.2 currents is unknown. In the present study, we determined that PKC directly phosphorylates the Kv4.2 channel protein. In vitro phosphorylation of the intracellular N- and C-termini of Kv4.2 GST (glutathione transferase) tagged fusion protein revealed that the C-terminal of Kv4.2 was phosphorylated by PKC, whereas the N-terminal was not. Amino acid mapping and site-directed mutagenesis revealed that the phosphorylated residues on the Kv4.2 C-terminal were Ser447 and Ser537. A phospho-site-specific antibody showed that phosphorylation at the Ser537 site was increased in the hippocampus in response to PKC activation. Surface biotinylation experiments revealed that mutation to alanine of both Ser447 and Ser537 in order to block phosphorylation at both of the PKC sites increased surface expression compared with wild-type Kv4.2. Electrophysiological recordings of the wild-type and both the alanine and aspartate mutant Kv4.2 channels expressed with KChIP3 (Kv4 channel-interacting protein 3) revealed no significant difference in the half-activation or half-inactivation voltage of the channel. Interestingly, Ser537 lies within a possible ERK (extracellular-signal-regulated kinase)/MAPK (mitogen-activated protein kinase) recognition (docking) domain in the Kv4.2 C-terminal sequence. We found that phosphorylation of Kv4.2 by PKC enhanced ERK phosphorylation of the channel in vitro. These findings suggest the possibility that Kv4.2 is a locus for PKC and ERK cross-talk.
Adams,
The A-type potassium channel Kv4.2 is a substrate for the mitogen-activated protein kinase ERK.
2000, Pubmed
Adams,
The A-type potassium channel Kv4.2 is a substrate for the mitogen-activated protein kinase ERK.
2000,
Pubmed Anderson,
Kv4.2 phosphorylation by cyclic AMP-dependent protein kinase.
2000,
Pubmed Apkon,
Alpha 1-adrenergic agonists selectively suppress voltage-dependent K+ current in rat ventricular myocytes.
1988,
Pubmed Blom,
Prediction of post-translational glycosylation and phosphorylation of proteins from the amino acid sequence.
2004,
Pubmed Boland,
Protein kinase C inhibits Kv1.1 potassium channel function.
1999,
Pubmed
,
Xenbase Braun,
Intracellular mechanisms for alpha 1-adrenergic regulation of the transient outward current in rabbit atrial myocytes.
1990,
Pubmed Burkhalter,
Differential expression of I(A) channel subunits Kv4.2 and Kv4.3 in mouse visual cortical neurons and synapses.
2006,
Pubmed Cantrell,
Neuromodulation of Na+ channels: an unexpected form of cellular plasticity.
2001,
Pubmed Chen,
Studies with synthetic peptide substrates derived from the neuronal protein neurogranin reveal structural determinants of potency and selectivity for protein kinase C.
1993,
Pubmed Chen,
Deletion of Kv4.2 gene eliminates dendritic A-type K+ current and enhances induction of long-term potentiation in hippocampal CA1 pyramidal neurons.
2006,
Pubmed Covarrubias,
Elimination of rapid potassium channel inactivation by phosphorylation of the inactivation gate.
1994,
Pubmed
,
Xenbase Dixon,
Quantitative analysis of potassium channel mRNA expression in atrial and ventricular muscle of rats.
1994,
Pubmed Dixon,
Role of the Kv4.3 K+ channel in ventricular muscle. A molecular correlate for the transient outward current.
1996,
Pubmed Fedida,
Alpha 1-adrenoceptors in myocardium: functional aspects and transmembrane signaling mechanisms.
1993,
Pubmed Fedida,
Alpha-adrenergic modulation of the transient outward current in rabbit atrial myocytes.
1990,
Pubmed Guo,
Targeted deletion of Kv4.2 eliminates I(to,f) and results in electrical and molecular remodeling, with no evidence of ventricular hypertrophy or myocardial dysfunction.
2005,
Pubmed Hoffman,
Downregulation of transient K+ channels in dendrites of hippocampal CA1 pyramidal neurons by activation of PKA and PKC.
1998,
Pubmed Hoffman,
Neuromodulation of dendritic action potentials.
1999,
Pubmed Hu,
ERK integrates PKA and PKC signaling in superficial dorsal horn neurons. I. Modulation of A-type K+ currents.
2003,
Pubmed Hu,
The kv4.2 potassium channel subunit is required for pain plasticity.
2006,
Pubmed Isbrandt,
Gene structures and expression profiles of three human KCND (Kv4) potassium channels mediating A-type currents I(TO) and I(SA).
2000,
Pubmed Kong,
Isolation and characterization of the human gene encoding Ito: further diversity by alternative mRNA splicing.
1998,
Pubmed Moran,
Modulation of a Shaker potassium A-channel by protein kinase C activation.
1991,
Pubmed
,
Xenbase Nakamura,
Modulation of Kv4 channels, key components of rat ventricular transient outward K+ current, by PKC.
1997,
Pubmed
,
Xenbase Petrecca,
Localization and enhanced current density of the Kv4.2 potassium channel by interaction with the actin-binding protein filamin.
2000,
Pubmed Po,
Mechanism of alpha-adrenergic regulation of expressed hKv4.3 currents.
2001,
Pubmed Ren,
Regulation of surface localization of the small conductance Ca2+-activated potassium channel, Sk2, through direct phosphorylation by cAMP-dependent protein kinase.
2006,
Pubmed Roberson,
The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus.
1999,
Pubmed Rosenfeld,
In-gel digestion of proteins for internal sequence analysis after one- or two-dimensional gel electrophoresis.
1992,
Pubmed Schrader,
PKA modulation of Kv4.2-encoded A-type potassium channels requires formation of a supramolecular complex.
2002,
Pubmed
,
Xenbase Schrader,
ERK/MAPK regulates the Kv4.2 potassium channel by direct phosphorylation of the pore-forming subunit.
2006,
Pubmed
,
Xenbase Sharrocks,
Docking domains and substrate-specificity determination for MAP kinases.
2000,
Pubmed Shen,
Tetraethylammonium block of Slowpoke calcium-activated potassium channels expressed in Xenopus oocytes: evidence for tetrameric channel formation.
1994,
Pubmed
,
Xenbase Shibata,
A fundamental role for KChIPs in determining the molecular properties and trafficking of Kv4.2 potassium channels.
2003,
Pubmed Sweatt,
Mitogen-activated protein kinases in synaptic plasticity and memory.
2004,
Pubmed Woodgett,
Substrate specificity of protein kinase C. Use of synthetic peptides corresponding to physiological sites as probes for substrate recognition requirements.
1986,
Pubmed Yuan,
Protein kinase modulation of dendritic K+ channels in hippocampus involves a mitogen-activated protein kinase pathway.
2002,
Pubmed
