shal potassium channels


Summary: A shaker subfamily of potassium channels that participate in transient outward potassium currents by activating at subthreshold MEMBRANE POTENTIALS, inactivating rapidly, and recovering from inactivation quickly.

Top Publications

  1. Bernard C, Anderson A, Becker A, Poolos N, Beck H, Johnston D. Acquired dendritic channelopathy in temporal lobe epilepsy. Science. 2004;305:532-5 pubmed
    ..Kinase inhibition partly reversed dendritic excitability to control levels. Such acquired channelopathy is likely to amplify neuronal activity and may contribute to the initiation and/or propagation of seizures in TLE. ..
  2. Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation. 2004;110:1731-7 pubmed
    ..Randomized studies comparing these two therapies seem warranted. ..
  3. Hatano N, Ohya S, Muraki K, Clark R, Giles W, Imaizumi Y. Two arginines in the cytoplasmic C-terminal domain are essential for voltage-dependent regulation of A-type K+ current in the Kv4 channel subfamily. J Biol Chem. 2004;279:5450-9 pubmed
    ..In conclusion, the two arginines in the cytosolic C-terminal domain of alpha-subunits of Kv4 subfamily strongly regulate the voltage dependence of channel activation, inactivation, and recovery. ..
  4. Kim L, Furst J, Butler M, Xu S, Grigorieff N, Goldstein S. Ito channels are octomeric complexes with four subunits of each Kv4.2 and K+ channel-interacting protein 2. J Biol Chem. 2004;279:5549-54 pubmed
    ..A complex has 4 subunits of each type, a stoichiometry expected for other channels employing neuronal calcium sensing beta-subunits. ..
  5. O Callaghan D, Hasdemir B, Leighton M, Burgoyne R. Residues within the myristoylation motif determine intracellular targeting of the neuronal Ca2+ sensor protein KChIP1 to post-ER transport vesicles and traffic of Kv4 K+ channels. J Cell Sci. 2003;116:4833-45 pubmed
    ..We suggest that KChIP1 is targeted by its myristoylation motif to post-ER transport vesicles where it could interact with and regulate the traffic of Kv4 channels to the plasma membrane under the influence of localised Ca2+ signals. ..
  6. Jerng H, Pfaffinger P. Incorporation of DPP6a and DPP6K variants in ternary Kv4 channel complex reconstitutes properties of A-type K current in rat cerebellar granule cells. PLoS ONE. 2012;7:e38205 pubmed publisher
    ..Our results support the hypothesis that the precise expression and co-assembly of different auxiliary subunit variants are important factors in shaping the I(SA) functional properties in specific neuronal populations. ..
  7. Sutton G, Patterson L, Berthoud H. Extracellular signal-regulated kinase 1/2 signaling pathway in solitary nucleus mediates cholecystokinin-induced suppression of food intake in rats. J Neurosci. 2004;24:10240-7 pubmed
  8. Jinno S, Jeromin A, Kosaka T. Postsynaptic and extrasynaptic localization of Kv4.2 channels in the mouse hippocampal region, with special reference to targeted clustering at gabaergic synapses. Neuroscience. 2005;134:483-94 pubmed
    ..The present findings indicate targeted clustering of Kv4.2 potassium channels at postsynaptic sites of GABAergic synapses and extrasynaptic sites, and provide some key to understand their role in the hippocampal region. ..
  9. Burkhalter A, Gonchar Y, Mellor R, Nerbonne J. Differential expression of I(A) channel subunits Kv4.2 and Kv4.3 in mouse visual cortical neurons and synapses. J Neurosci. 2006;26:12274-82 pubmed
    ..Thus, the synapse-specific distribution of Kv4 channels functions to optimize dendritic excitation and the association between presynaptic and postsynaptic activity. ..

More Information


  1. Gardoni F, Mauceri D, Marcello E, Sala C, Di Luca M, Jeromin A. SAP97 directs the localization of Kv4.2 to spines in hippocampal neurons: regulation by CaMKII. J Biol Chem. 2007;282:28691-9 pubmed
    ..2. These results show that SAP97-CaMKII pathway plays an important role for the trafficking of Kv4.2 to dendrites and spines. ..
  2. Shahidullah M, Covarrubias M. The link between ion permeation and inactivation gating of Kv4 potassium channels. Biophys J. 2003;84:928-41 pubmed
    ..By examining possible changes in ionic selectivity and the influence of elevating the external K(+) concentration, additional experiments did not support the presence of C-type inactivation in Kv4 channels. ..
  3. Zhang Y, Wu W, Sun H, Deng X, Cheng L, Li X, et al. Modulation of human cardiac transient outward potassium current by EGFR tyrosine kinase and Src-family kinases. Cardiovasc Res. 2012;93:424-33 pubmed publisher
  4. Menegola M, Trimmer J. Unanticipated region- and cell-specific downregulation of individual KChIP auxiliary subunit isotypes in Kv4.2 knock-out mouse brain. J Neurosci. 2006;26:12137-42 pubmed
    ..2-dependent effects on KChIPs. The impact of Kv4.2 deletion on KChIP expression also supports the major role of KChIPs as auxiliary subunits of Kv4 channels. ..
  5. Kaulin Y, De Santiago Castillo J, Rocha C, Covarrubias M. Mechanism of the modulation of Kv4:KChIP-1 channels by external K+. Biophys J. 2008;94:1241-51 pubmed
    ..Regulation of Kv4 channel inactivation by hyperkalemia may help to explain the pathophysiology of electrolyte imbalances in excitable tissues. ..
  6. Plant L, Webster N, Boyle J, Ramsden M, Freir D, Peers C, et al. Amyloid beta peptide as a physiological modulator of neuronal 'A'-type K+ current. Neurobiol Aging. 2006;27:1673-83 pubmed
    ..Thus Abeta is not only involved in Alzheimer pathology, but is also an important physiological regulator of ion channel expression and hence neuronal excitability. ..
  7. Ryglewski S, Duch C. Shaker and Shal mediate transient calcium-independent potassium current in a Drosophila flight motoneuron. J Neurophysiol. 2009;102:3673-88 pubmed publisher
    ..These data can now be used to investigate the roles of Shaker and Shal for motoneuron intrinsic properties, synaptic integration, and spiking output during behavior by targeted genetic manipulations. ..
  8. Hatano N, Ohya S, Imaizumi Y. Functional interaction between KChIP1 and GFP-fused Kv4.3L co-expressed in HEK293 cells. Pflugers Arch. 2002;444:80-8 pubmed
    ..3L at all. The trafficking of Kv4.3L by KChIP1 to the cell membrane was visualized with GFP fusion to the N-terminus without any significant modification of changes in channel kinetics and density. ..
  9. Amberg G, Koh S, Imaizumi Y, Ohya S, Sanders K. A-type potassium currents in smooth muscle. Am J Physiol Cell Physiol. 2003;284:C583-95 pubmed
    ..This approach should also aid in the identification of areas of research requiring further attention. ..
  10. Varga A, Yuan L, Anderson A, Schrader L, Wu G, Gatchel J, et al. Calcium-calmodulin-dependent kinase II modulates Kv4.2 channel expression and upregulates neuronal A-type potassium currents. J Neurosci. 2004;24:3643-54 pubmed
    ..Thus CaMKII can directly modulate neuronal excitability by increasing cell-surface expression of A-type K(+) channels. ..
  11. Kawada H, Niwano S, Niwano H, Yumoto Y, Wakisaka Y, Yuge M, et al. Tumor necrosis factor-alpha downregulates the voltage gated outward K+ current in cultured neonatal rat cardiomyocytes: a possible cause of electrical remodeling in diseased hearts. Circ J. 2006;70:605-9 pubmed
  12. Kim J, Nadal M, Clemens A, Baron M, Jung S, Misumi Y, et al. Kv4 accessory protein DPPX (DPP6) is a critical regulator of membrane excitability in hippocampal CA1 pyramidal neurons. J Neurophysiol. 2008;100:1835-47 pubmed publisher
    ..The Kv4 auxiliary subunit DPPX thus acts to increase neuronal responsiveness and enhance signal precision by advancing AP initiation and accelerating both the rise and repolarization of APs. ..
  13. Dougherty K, Tu L, Deutsch C, Covarrubias M. The dipeptidyl-aminopeptidase-like protein 6 is an integral voltage sensor-interacting beta-subunit of neuronal K(V)4.2 channels. Channels (Austin). 2009;3:122-8 pubmed
    ..Understanding these interactions may shed light on the pathophysiology of recently identified human disorders associated with mutations affecting the dpp6 gene. ..
  14. Pioletti M, Findeisen F, Hura G, Minor D. Three-dimensional structure of the KChIP1-Kv4.3 T1 complex reveals a cross-shaped octamer. Nat Struct Mol Biol. 2006;13:987-95 pubmed
    ..Together, the data resolve how Kv4 channels and KChIPs interact and provide a framework for understanding how KChIPs modulate Kv4 function. ..
  15. Nadal M, Amarillo Y, Vega Saenz de Miera E, Rudy B. Differential characterization of three alternative spliced isoforms of DPPX. Brain Res. 2006;1094:1-12 pubmed
    ..The emerging diversity of DPPX splice variants, differing only in the N-terminus of the protein, opens up intriguing possibilities for the modulation of Kv4 channels. ..
  16. Gasque G, Labarca P, Reynaud E, Darszon A. Shal and shaker differential contribution to the K+ currents in the Drosophila mushroom body neurons. J Neurosci. 2005;25:2348-58 pubmed
    ..To our surprise, the experimental data also indicate that Shaker channels segregate to a minor fraction of MB neuronal somata (20-30%), and that Shal channels contribute the somatic A-type current in the majority of MBNs. ..
  17. Shibasaki K, Nakahira K, Trimmer J, Shibata R, Akita M, Watanabe S, et al. Mossy fibre contact triggers the targeting of Kv4.2 potassium channels to dendrites and synapses in developing cerebellar granule neurons. J Neurochem. 2004;89:897-907 pubmed
    ..2 channels is dynamically regulated by synaptic activity. This activity-dependent regulation of Kv4.2 localization provides a crucial yet dynamic link between synaptic activity and dendritic excitability. ..
  18. Marionneau C, Carrasquillo Y, Norris A, Townsend R, Isom L, Link A, et al. The sodium channel accessory subunit Nav?1 regulates neuronal excitability through modulation of repolarizing voltage-gated K? channels. J Neurosci. 2012;32:5716-27 pubmed publisher
    ..2-encoded current densities. Together, the results presented here identify Nav?1 as a component of native neuronal Kv4.2-encoded I(A) channel complexes and a novel regulator of I(A) channel densities and neuronal excitability. ..
  19. Kunjilwar K, Strang C, DeRubeis D, Pfaffinger P. KChIP3 rescues the functional expression of Shal channel tetramerization mutants. J Biol Chem. 2004;279:54542-51 pubmed
  20. Fawcett G, Santi C, Butler A, Harris T, Covarrubias M, Salkoff L. Mutant analysis of the Shal (Kv4) voltage-gated fast transient K+ channel in Caenorhabditis elegans. J Biol Chem. 2006;281:30725-35 pubmed
    ..SHL-1 channels are apparently important in fine-tuning complex behaviors, such as mating, that play a crucial role in the survival and propagation of the species. ..
  21. Cai X, Liang C, Muralidharan S, Muralidharan S, Kao J, Tang C, et al. Unique roles of SK and Kv4.2 potassium channels in dendritic integration. Neuron. 2004;44:351-64 pubmed
    ..SK channels thus underlie repolarization of dendritic plateau potentials, whereas Kv4.2 channels confine these potentials to single dendritic branches, and both act in concert to regulate synaptic integration. ..
  22. Strassle B, Menegola M, Rhodes K, Trimmer J. Light and electron microscopic analysis of KChIP and Kv4 localization in rat cerebellar granule cells. J Comp Neurol. 2005;484:144-55 pubmed
    ..2 and KChIP1, and perhaps also KChIP3 and 4, play a critical role in regulating postsynaptic excitability at the cerebellar mossy-fiber/granule cell synapse. ..
  23. Li G, Du X, Siow Y, O K, Tse H, Lau C. Calcium-activated transient outward chloride current and phase 1 repolarization of swine ventricular action potential. Cardiovasc Res. 2003;58:89-98 pubmed
    ..The results indicate that 4-AP-sensitive I(to1) is not expressed, and only Ca(2+)-activated I(to2) is present in pig cardiac cells, which contributes importantly to the phase 1 repolarization of ventricular APs in this species. ..
  24. Scannevin R, Wang K, Jow F, Megules J, Kopsco D, Edris W, et al. Two N-terminal domains of Kv4 K(+) channels regulate binding to and modulation by KChIP1. Neuron. 2004;41:587-98 pubmed
  25. Schrader L, Birnbaum S, Nadin B, Ren Y, Bui D, Anderson A, et al. ERK/MAPK regulates the Kv4.2 potassium channel by direct phosphorylation of the pore-forming subunit. Am J Physiol Cell Physiol. 2006;290:C852-61 pubmed
    ..Overall these studies provide new insights into the structure-function relationships for MAPK regulation of membrane ion channels. ..
  26. Kollo M, Holderith N, Nusser Z. Novel subcellular distribution pattern of A-type K+ channels on neuronal surface. J Neurosci. 2006;26:2684-91 pubmed
    ..Based on our results and on the known properties of A-type K+ channels, we propose that strategically clustered K+ channels at unique membrane specializations could mediate a novel type of communication between nerve cells. ..
  27. Seikel E, Trimmer J. Convergent modulation of Kv4.2 channel alpha subunits by structurally distinct DPPX and KChIP auxiliary subunits. Biochemistry. 2009;48:5721-30 pubmed publisher
    ..2 alone. In conclusion, transmembrane DPPX-S and cytoplasmic KChIPs, despite having distinct structures and binding sites on Kv4.2, exert similar effects on Kv4.2 trafficking, but distinct effects on Kv4.2 gating. ..
  28. Strang C, Kunjilwar K, DeRubeis D, Peterson D, Pfaffinger P. The role of Zn2+ in Shal voltage-gated potassium channel formation. J Biol Chem. 2003;278:31361-71 pubmed
    ..Therefore, zinc-mediated tetramerization also is a physiologically important event for full-length functional channel formation. ..
  29. Panama B, Latour Villamil D, Farman G, Zhao D, Bolz S, Kirshenbaum L, et al. Nuclear factor kappaB downregulates the transient outward potassium current I(to,f) through control of KChIP2 expression. Circ Res. 2011;108:537-43 pubmed publisher
    ..NF-?B regulates KChIP2 and Kv4.2 expression. The reductions in I(to,f) observed following ?-adrenergic receptor stimulation or tumor necrosis factor ? application require NF-?B-dependent decreases in KChIP2 expression. ..
  30. Grandy S, Trépanier Boulay V, Fiset C. Postnatal development has a marked effect on ventricular repolarization in mice. Am J Physiol Heart Circ Physiol. 2007;293:H2168-77 pubmed
    ..Overall, it appears that, in mouse ventricle, developmental changes in APD are likely attributable to increases in I(to), I(ss), and I(K1), whereas the role of I(Kur) during postnatal development appears to be less critical to APD. ..
  31. Lugo J, Brewster A, Spencer C, Anderson A. Kv4.2 knockout mice have hippocampal-dependent learning and memory deficits. Learn Mem. 2012;19:182-9 pubmed publisher
    ..Overall, our findings add to the growing body of evidence, suggesting an important role for Kv4.2 channels in hippocampal-dependent learning and memory...
  32. Wang S, Patel S, Qu Y, Hua P, Strauss H, Morales M. Kinetic properties of Kv4.3 and their modulation by KChIP2b. Biochem Biophys Res Commun. 2002;295:223-9 pubmed
    ..6-fold in the wild-type channel and 5.7-fold in Kv4.3 [V(399,401)I]. These data suggest that inner pore structure is an important factor in the modulatory effects of KChIP2b on Kv4.3 K(+) channels. ..
  33. Anderson D, Mehaffey W, Iftinca M, Rehak R, Engbers J, Hameed S, et al. Regulation of neuronal activity by Cav3-Kv4 channel signaling complexes. Nat Neurosci. 2010;13:333-7 pubmed publisher
    ..The widespread expression of these channels and accessory proteins indicates that the Cav3-Kv4 signaling complex is important for the function of a wide range of electrically excitable cells. ..
  34. Morohashi Y, Hatano N, Ohya S, Takikawa R, Watabiki T, Takasugi N, et al. Molecular cloning and characterization of CALP/KChIP4, a novel EF-hand protein interacting with presenilin 2 and voltage-gated potassium channel subunit Kv4. J Biol Chem. 2002;277:14965-75 pubmed
    ..Taken together, CALP/KChIP4 is a novel EF-hand protein interacting with PS as well as with Kv4 that may modulate functions of a subset of membrane proteins in brain. ..
  35. Kaulin Y, De Santiago Castillo J, Rocha C, Nadal M, Rudy B, Covarrubias M. The dipeptidyl-peptidase-like protein DPP6 determines the unitary conductance of neuronal Kv4.2 channels. J Neurosci. 2009;29:3242-51 pubmed publisher
    ..These observations may help to understand the molecular basis of neurological disorders correlated with recently identified human mutations in the dpp6 gene. ..
  36. Foeger N, Norris A, Wren L, Nerbonne J. Augmentation of Kv4.2-encoded currents by accessory dipeptidyl peptidase 6 and 10 subunits reflects selective cell surface Kv4.2 protein stabilization. J Biol Chem. 2012;287:9640-50 pubmed publisher
    ..2. ..
  37. Covarrubias M, Bhattacharji A, De Santiago Castillo J, Dougherty K, Kaulin Y, Na Phuket T, et al. The neuronal Kv4 channel complex. Neurochem Res. 2008;33:1558-67 pubmed publisher
    ..These studies are shedding new light on the molecular bases of I(SA) function and regulation. ..
  38. Zagha E, Ozaita A, Chang S, Nadal M, Lin U, Saganich M, et al. DPP10 modulates Kv4-mediated A-type potassium channels. J Biol Chem. 2005;280:18853-61 pubmed
    ..Chimeras of DPPX and DPP10, but not DPPIV, were able to modulate the properties of Kv4.2 channels, highlighting the importance of the intracellular and transmembrane domains in this activity. ..
  39. Zhou W, Qian Y, Kunjilwar K, Pfaffinger P, Choe S. Structural insights into the functional interaction of KChIP1 with Shal-type K(+) channels. Neuron. 2004;41:573-86 pubmed
    ..Site-specific mutagenesis combined with functional characterization shows that those interactions mediated by alpha1 and H10 are essential to the modulation of Kv4.2 by KChIPs. ..
  40. Nadin B, Pfaffinger P. Dipeptidyl peptidase-like protein 6 is required for normal electrophysiological properties of cerebellar granule cells. J Neurosci. 2010;30:8551-65 pubmed publisher
    ..Overall, DPP6 expression seems to be critical for the expression of a high-frequency electrophysiological phenotype in CG cells by increasing leak conductance, A-type current levels and kinetics, and Na(+) current amplitude. ..
  41. Birnbaum S, Varga A, Yuan L, Anderson A, Sweatt J, Schrader L. Structure and function of Kv4-family transient potassium channels. Physiol Rev. 2004;84:803-33 pubmed
    ..Finally, the pathophysiology that may arise from dysregulation of these channels is also reviewed. ..
  42. Xiong H, Kovacs I, Zhang Z. Differential distribution of KChIPs mRNAs in adult mouse brain. Brain Res Mol Brain Res. 2004;128:103-11 pubmed
    ..2 and Kv4.3 have been reported. These findings support the likelihood of functional interactions between KChIPs and Kv4 K(+) channels in brain. ..
  43. Strop P, Bankovich A, Hansen K, Garcia K, Brunger A. Structure of a human A-type potassium channel interacting protein DPPX, a member of the dipeptidyl aminopeptidase family. J Mol Biol. 2004;343:1055-65 pubmed
    ..However, the arrangement of residues is inconsistent with that of canonical serine proteases and DPPX is unlikely to function as a protease (dipeptidyl aminopeptidase). ..
  44. Zhao C, Wang L, Netoff T, Yuan L. Dendritic mechanisms controlling the threshold and timing requirement of synaptic plasticity. Hippocampus. 2011;21:288-97 pubmed publisher
    ..In conclusion, dendritic A-type and Ca(2+) -activated K(+) channels dually regulate the timing-dependence and thresholds of synaptic plasticity in an additive way. ..
  45. Jerng H, Dougherty K, Covarrubias M, Pfaffinger P. A novel N-terminal motif of dipeptidyl peptidase-like proteins produces rapid inactivation of KV4.2 channels by a pore-blocking mechanism. Channels (Austin). 2009;3:448-61 pubmed
    ..This mechanism may offer an attractive target for novel pharmacological interventions directed at impairing I(SA) inactivation and reducing neuronal excitability. ..
  46. Shimoni Y, Liu X. Role of PKC in autocrine regulation of rat ventricular K+ currents by angiotensin and endothelin. Am J Physiol Heart Circ Physiol. 2003;284:H1168-81 pubmed
  47. Wang G, Strang C, Pfaffinger P, Covarrubias M. Zn2+-dependent redox switch in the intracellular T1-T1 interface of a Kv channel. J Biol Chem. 2007;282:13637-47 pubmed
    ..We propose that the interfacial T1 Zn(2+) site of Kv4 channels acts as a Zn(2+)-dependent redox switch that may regulate the activity of neuronal and cardiac A-type K(+) currents under physiological and pathological conditions. ..
  48. Hammond R, Lin L, Sidorov M, Wikenheiser A, Hoffman D. Protein kinase a mediates activity-dependent Kv4.2 channel trafficking. J Neurosci. 2008;28:7513-9 pubmed publisher
    ..2 (S552A) prevented the AMPA-induced internalization of Kv4.2. Together, these data demonstrate that Kv4.2 activity-dependent internalization requires PKA phosphorylation of Kv4.2 at serine 522. ..
  49. Bähring R, Covarrubias M. Mechanisms of closed-state inactivation in voltage-gated ion channels. J Physiol. 2011;589:461-79 pubmed publisher
    ..Kv4 channel CSI may efficiently exploit the dynamics of the subthreshold membrane potential to regulate spiking properties in excitable tissues. ..
  50. Nanao M, Zhou W, Pfaffinger P, Choe S. Determining the basis of channel-tetramerization specificity by x-ray crystallography and a sequence-comparison algorithm: Family Values (FamVal). Proc Natl Acad Sci U S A. 2003;100:8670-5 pubmed
    ..The structural basis of this assembly discrimination was elucidated by determining the crystal structure of the Kv4 T1 domain and comparing it to the Kv3 T1 domain. ..
  51. Giudicessi J, Ye D, Kritzberger C, Nesterenko V, Tester D, Antzelevitch C, et al. Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death. Hum Mutat. 2012;33:989-97 pubmed publisher
    ..6-fold, indicating a mixed electrophysiological phenotype. This is the first report indicating that KCND3 may serve as a rare genetic substrate in the pathogenesis of SUDS but not SIDS cases. ..
  52. Hu H, Alter B, Carrasquillo Y, Qiu C, Gereau R. Metabotropic glutamate receptor 5 modulates nociceptive plasticity via extracellular signal-regulated kinase-Kv4.2 signaling in spinal cord dorsal horn neurons. J Neurosci. 2007;27:13181-91 pubmed
    ..2-containing potassium channels in dorsal horn neurons. This modulation may contribute to nociceptive plasticity and central sensitization associated with chronic inflammatory pain conditions. ..
  53. Cui Y, Liang P, Wang K. Enhanced trafficking of tetrameric Kv4.3 channels by KChIP1 clamping. Neurochem Res. 2008;33:2078-84 pubmed publisher
    ..The results also suggest that formation of octameric Kv4 and KChIP complex by KChIPs clamping takes place before their trafficking to final destination on the cell surface. ..