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Channels (Austin)
2009 Nov 01;36:448-61. doi: 10.4161/chan.3.6.10216.
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A novel N-terminal motif of dipeptidyl peptidase-like proteins produces rapid inactivation of KV4.2 channels by a pore-blocking mechanism.
Jerng HH
,
Dougherty K
,
Covarrubias M
,
Pfaffinger PJ
.
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The somatodendritic subthreshold A-type K(+) current in neurons (I(SA)) depends on its kinetic and voltage-dependent properties to regulate membrane excitability, action potential repetitive firing, and signal integration. Key functional properties of the K(V)4 channel complex underlying I(SA) are determined by dipeptidyl peptidase-like proteins known as dipeptidyl peptidase 6 (DPP6) and dipeptidyl peptidase 10 (DPP10). Among the multiple known DPP10 isoforms with alternative N-terminal sequences, DPP10a confers exceptionally fast inactivation to K(V)4.2 channels. To elucidate the molecular basis of this fast inactivation, we investigated the structure-function relationship of the DPP10a N-terminal region and its interaction with the K(V)4.2 channel. Here, we show that DPP10a shares a conserved N-terminal sequence (MNQTA) with DPP6a (aka DPP6-E), which also induces fast inactivation. Deletion of the NQTA sequence in DPP10a eliminates this dramatic fast inactivation, and perfusion of MNQTA peptide to the cytoplasmic face of inside-out patches inhibits the K(V)4.2 current. DPP10a-induced fast inactivation exhibits competitive interactions with internally applied tetraethylammonium (TEA), and elevating the external K(+) concentration accelerates recovery from DPP10a-mediated fast inactivation. These results suggest that fast inactivation induced by DPP10a or DPP6a is mediated by a common N-terminal inactivation motif via a pore-blocking mechanism. This mechanism may offer an attractive target for novel pharmacological interventions directed at impairing I(SA) inactivation and reducing neuronal excitability.
Amarillo,
Ternary Kv4.2 channels recapitulate voltage-dependent inactivation kinetics of A-type K+ channels in cerebellar granule neurons.
2008, Pubmed
Amarillo,
Ternary Kv4.2 channels recapitulate voltage-dependent inactivation kinetics of A-type K+ channels in cerebellar granule neurons.
2008,
Pubmed
An,
Modulation of A-type potassium channels by a family of calcium sensors.
2000,
Pubmed
,
Xenbase
Bähring,
Kinetic analysis of open- and closed-state inactivation transitions in human Kv4.2 A-type potassium channels.
2001,
Pubmed
Beck,
Kv4 channels exhibit modulation of closed-state inactivation in inside-out patches.
2001,
Pubmed
,
Xenbase
Birnbaum,
Structure and function of Kv4-family transient potassium channels.
2004,
Pubmed
Chahine,
Functional expression and properties of the human skeletal muscle sodium channel.
1994,
Pubmed
,
Xenbase
Choi,
Tetraethylammonium blockade distinguishes two inactivation mechanisms in voltage-activated K+ channels.
1991,
Pubmed
Covarrubias,
The neuronal Kv4 channel complex.
2008,
Pubmed
Covarrubias,
Elimination of rapid potassium channel inactivation by phosphorylation of the inactivation gate.
1994,
Pubmed
,
Xenbase
Cronin,
A genome-wide association study of sporadic ALS in a homogenous Irish population.
2008,
Pubmed
Demo,
The inactivation gate of the Shaker K+ channel behaves like an open-channel blocker.
1991,
Pubmed
Dougherty,
A dipeptidyl aminopeptidase-like protein remodels gating charge dynamics in Kv4.2 channels.
2006,
Pubmed
,
Xenbase
Dougherty,
The dipeptidyl-aminopeptidase-like protein 6 is an integral voltage sensor-interacting beta-subunit of neuronal K(V)4.2 channels.
2009,
Pubmed
Faraldo-Gómez,
Mechanism of intracellular block of the KcsA K+ channel by tetrabutylammonium: insights from X-ray crystallography, electrophysiology and replica-exchange molecular dynamics simulations.
2007,
Pubmed
Gebauer,
N-type inactivation features of Kv4.2 channel gating.
2004,
Pubmed
Heinemann,
Functional characterization of Kv channel beta-subunits from rat brain.
1996,
Pubmed
,
Xenbase
Hoshi,
Biophysical and molecular mechanisms of Shaker potassium channel inactivation.
1990,
Pubmed
,
Xenbase
Hough,
Rump white inversion in the mouse disrupts dipeptidyl aminopeptidase-like protein 6 and causes dysregulation of Kit expression.
1998,
Pubmed
Jerng,
DPP10 splice variants are localized in distinct neuronal populations and act to differentially regulate the inactivation properties of Kv4-based ion channels.
2007,
Pubmed
,
Xenbase
Jerng,
Molecular physiology and modulation of somatodendritic A-type potassium channels.
2004,
Pubmed
Jerng,
Modulation of Kv4.2 channel expression and gating by dipeptidyl peptidase 10 (DPP10).
2004,
Pubmed
,
Xenbase
Jerng,
Inactivation and pharmacological properties of sqKv1A homotetramers in Xenopus oocytes cannot account for behavior of the squid "delayed rectifier" K(+) conductance.
2002,
Pubmed
,
Xenbase
Jerng,
Inactivation gating of Kv4 potassium channels: molecular interactions involving the inner vestibule of the pore.
1999,
Pubmed
,
Xenbase
Jerng,
Multiprotein assembly of Kv4.2, KChIP3 and DPP10 produces ternary channel complexes with ISA-like properties.
2005,
Pubmed
,
Xenbase
Jurman,
Visual identification of individual transfected cells for electrophysiology using antibody-coated beads.
1994,
Pubmed
Kaulin,
Mechanism of the modulation of Kv4:KChIP-1 channels by external K+.
2008,
Pubmed
,
Xenbase
Lenaeus,
Structural basis of TEA blockade in a model potassium channel.
2005,
Pubmed
López-Barneo,
Effects of external cations and mutations in the pore region on C-type inactivation of Shaker potassium channels.
1993,
Pubmed
,
Xenbase
Lu,
Disruption of Kv1.1 N-type inactivation by novel small molecule inhibitors (disinactivators).
2008,
Pubmed
Maffie,
Weighing the evidence for a ternary protein complex mediating A-type K+ currents in neurons.
2008,
Pubmed
Maffie,
A novel DPP6 isoform (DPP6-E) can account for differences between neuronal and reconstituted A-type K(+) channels.
2009,
Pubmed
Marshall,
Structural variation of chromosomes in autism spectrum disorder.
2008,
Pubmed
Murrell-Lagnado,
Energetics of Shaker K channels block by inactivation peptides.
1993,
Pubmed
,
Xenbase
Murrell-Lagnado,
Interactions of amino terminal domains of Shaker K channels with a pore blocking site studied with synthetic peptides.
1993,
Pubmed
,
Xenbase
Nadal,
Differential characterization of three alternative spliced isoforms of DPPX.
2006,
Pubmed
,
Xenbase
Nadal,
The CD26-related dipeptidyl aminopeptidase-like protein DPPX is a critical component of neuronal A-type K+ channels.
2003,
Pubmed
,
Xenbase
O'Leary,
Internal block of human heart sodium channels by symmetrical tetra-alkylammoniums.
1994,
Pubmed
Pruunsild,
Structure, alternative splicing, and expression of the human and mouse KCNIP gene family.
2005,
Pubmed
Ruppersberg,
Cloned neuronal IK(A) channels reopen during recovery from inactivation.
1991,
Pubmed
Saito,
Voltage-gated transient outward currents in neurons with different firing patterns in rat superior colliculus.
2000,
Pubmed
Takimoto,
Species and tissue differences in the expression of DPPY splicing variants.
2006,
Pubmed
Tang,
Role of an S4-S5 linker in sodium channel inactivation probed by mutagenesis and a peptide blocker.
1996,
Pubmed
Taylor,
The classification of amino acid conservation.
1986,
Pubmed
Tseng,
Differential effects of elevating [K]o on three transient outward potassium channels. Dependence on channel inactivation mechanisms.
1992,
Pubmed
,
Xenbase
van Es,
Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis.
2008,
Pubmed
van Es,
Dpp6 is associated with susceptibility to progressive spinal muscular atrophy.
2009,
Pubmed
Wallner,
Molecular basis of fast inactivation in voltage and Ca2+-activated K+ channels: a transmembrane beta-subunit homolog.
1999,
Pubmed
,
Xenbase
Wang,
Structural basis for modulation of Kv4 K+ channels by auxiliary KChIP subunits.
2007,
Pubmed
,
Xenbase
Yohannan,
Crystallographic study of the tetrabutylammonium block to the KcsA K+ channel.
2007,
Pubmed
Zhang,
Disinactivation of N-type inactivation of voltage-gated K channels by an erbstatin analogue.
2004,
Pubmed
,
Xenbase
Zhou,
Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors.
2001,
Pubmed
,
Xenbase
