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At least 19 recordsLinked to original sources
PubMed2003

Analysis of phosphorylation-dependent modulation of Kv1.1 potassium channels.

The voltage-gated potassium channel Kv1.1 contains phosphorylation sites for protein kinase A (PKA) and protein kinase C (PKC). To study Kv1.1 protein expression and cellular distribution in regard to its level of phosphorylation, the effects of PKA and PKC activation on Kv1.1 were investigated in HEK 293 cells stably transfected with Kv1.1 (HEK 293/1). Without kinase activation, HEK 293/1 cells carry unphosphorylated Kv1.1 protein in the plasma membranes, whereas large amounts of phosphorylated and unphosphorylated Kv1.1 protein were located intracellularly. Activation of PKA resulted in phosphorylation of intracellular Kv1.1 protein, followed by a rapid translocation of Kv1.1 into the plasma membrane. Patch-clamp analysis revealed an increase in current amplitude upon PKA activation and demonstrated differences in the voltage dependence of current activation between unphosphorylated and phosphorylated Kv1.1 channels. In contrast to PKA, even prolonged activation of PKC did not lead to direct phosphorylation of Kv1.1, but induced Kv1.1 protein synthesis. Thus, protein kinases have direct and indirect effects on the functional expression of voltage-gated potassium channels. Our data suggest that the synergistic action of protein kinases may play an important role in the fine-tuning of Kv channel function.

Antibodies, Monoclonal↗
PubMed2002

Episodic ataxia type 1 mutations in the human Kv1.1 potassium channel alter hKvbeta 1-induced N-type inactivation.

Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder affecting both central and peripheral nerve function, causing attacks of imbalance and uncontrolled movements. Genetic linkage studies have identified mutations in the gene encoding the voltage-gated delayed rectifier potassium channel Kv1.1 as underlying EA1. The EA1 mutations E325D and V408A, residing near the cytoplasmic ends of S5 and S6, respectively, induce an unstable open state, resulting in an approximately 10-fold increase in deactivation rates compared with wild-type (WT) channels. Coexpression of EA1 mutations with human Kvbeta1 (hKvbeta1) subunits in Xenopus oocytes yielded channels with altered rapid N-type inactivation. Compared with WT channels, inactivation was approximately twofold slower for homomeric E325D or V408A channels and 1.5-fold slower for heteromeric channels composed of two WT and two E325D or V408A subunits. Recovery from inactivation was approximately 10-fold faster for homomeric E325D or V408A channels and threefold to fourfold faster for heteromeric WT and E325D or V408A channels compared with WT channels. Currents during successive pulses 3 msec in duration given at a rate of 40 kHz decayed e-fold in approximately four pulses for homomeric E325D or V408A and approximately 2.5 pulses for heteromeric channels compared with approximately one pulse for WT channels. These results show that channels containing E325D or V408A subunits, which destabilize the open state, increase the rate of recovery from inactivation. The slower onset and more rapid recovery of hKvbeta1-induced inactivation in channels containing these EA1 subunits may affect temporal integration of action potential firing rates.

Action Potentials↗
PubMed1998

Hyperalgesia in mice lacking the Kv1.1 potassium channel gene.

Hyperalgesia and morphine induced antinociception were measured in mice lacking the gene for the Shaker-like voltage-gated potassium channel Kv1.1 alpha subunit. The effects of varying gene dosage were studied by comparing homozygous null (-/-) versus heterozygous (+/-) and wildtype (+/+) littermates. Hyperalgesia was measured using the paw flick assay, hot plate assay and formalin induced hind paw licking. It was observed that null mutant animals had significantly shorter latencies to response in the paw flick (36%) and hot plate (27%) assays while their licking times after hind paw injection of formalin was increased in both the first (74%) and second (65%) phases of the response compared to wildtype controls. Morphine induced antinociception in Kv1.1 null mutant animals was blunted. These studies indicate that Kv1.1 plays an important role in nociceptive and antinociceptive signaling pathways.

Animals↗
PubMed1999

Developmental seizure susceptibility of kv1.1 potassium channel knockout mice.

Potassium channels play a critical role in limiting neuronal excitability. Mutations in certain voltage-gated potassium channels have been associated with hyperexcitable phenotypes in both humans and animals. However, only recently have mutations in potassium channel genes (i.e. KCNQ2 and KCNQ3) been discovered in a human epilepsy, benign familial neonatal convulsions. Recently, it has been reported that mice lacking the voltage-gated Shaker-like potassium channel Kv1.1 alpha-subunit develop recurrent spontaneous seizures early in postnatal development. The clinical relevance of the Kv1.1 knockout mouse has been underscored by a recent report of epilepsy occurring in a family affected by mutations in the KCNA1 locus (the human homologue of Kv1.1) which typically cause episodic ataxia and myokymia. Here we summarize preliminary studies characterizing the developmental changes in seizure susceptibility and neuronal activation in the three genotypes of Kv1.1 mice (-/-, +/-, +/+). Using behavioral and immediate-early gene indicators of regional brain excitability, we have found that a seizure-sensitive predisposition exists in Kv1.1 -/- animals at a very young age (P10), before either spontaneous seizure activity or changes in c-fos mRNA expression can be demonstrated. Kv1.1 +/- mice, although behaviorally indistinguishable from wild types, also have an increased susceptibility to seizures at a similar early age. The Kv1. 1 knockout mouse possesses many features desirable in a developmental animal epilepsy model and represents a clinically relevant model of early-onset epilepsies.

Animals↗
PubMed2002

Potassium channels Kv1.1, Kv1.2 and Kv1.6 influence excitability of rat visceral sensory neurons.

Voltage-gated potassium channels, Kv1.1, Kv1.2 and Kv1.6, were identified as PCR products from mRNA prepared from nodose ganglia. Immunocytochemical studies demonstrated expression of the proteins in all neurons from ganglia of neonatal animals (postnatal days 0-3) and in 85-90 % of the neurons from older animals (postnatal days 21-60). In voltage clamp studies, alpha-dendrotoxin (alpha-DTX), a toxin with high specificity for these members of the Kv1 family, was used to examine their contribution to K(+) currents of the sensory neurons. alpha-DTX blocked current in both A- and C-type neurons. The current had characteristics of a delayed rectifier with activation positive to -50 mV and little inactivation during 250 ms pulses. In current-clamp experiments alpha-DTX, used to eliminate the current, had no effect on resting membrane potential and only small effects on the amplitude and duration of the action potential of A- and C-type neurons. However, there were prominent effects on excitability. alpha-DTX lowered the threshold for initiation of discharge in response to depolarizing current steps, reduced spike after-hyperpolarization and increased the frequency/pattern of discharge of A- and C-type neurons at membrane potentials above threshold. Model simulations were consistent with these experimental results and demonstrated how the other major K(+) currents function in response to the loss of the alpha-DTX-sensitive current to effect these changes in action potential wave shape and discharge.

Algorithms↗
PubMed2004

Molecular docking of the scorpion toxin Tc1 to the structural model of the voltage-gated potassium channel Kv1.1 from human Homo sapiens.

In this study, structural model of the pore loop region of the voltage-gated potassium channel Kv1.1 from human Homo sapiens was constructed based on the crystallographic structure of KcsA by structural homology. The pore loop region of Kv1.1 exhibits similar folds as that of KcsA. The structural feature of the selectivity filter of Kv1.1 is nearly identical to that of KcsA, whereas most of the structural variations occur in the turret as well as in the inner and outer helices. Molecular docking experiments of the scorpion toxin Tc1 from Tityus cambridgei to the outer vestibule of KcsA as well as Kv1.1 were subsequently performed with various initial Tc1 orientations. Tc1 was found to form the most stable complexes with these two K+ channels when the side chain of Lys14 occupies the pore of the selectivity filter through electrostatic interaction. Tc1 binds preferentially towards Kv1.1 than KcsA due to stronger hydrophobic and electrostatic interactions formed between the toxin and the selectivity filter and outer vestibule of Kv1.1. Furthermore, surface complementarity of the outer vestibules of the channels to the Tc1 spatial conformations also plays an important role in stabilizing both the Tc1/KcsA and Tc1/Kv1.1 complexes.

Amino Acid Sequence↗
PubMed2001

Episodic ataxia type-1 mutations in the Kv1.1 potassium channel display distinct folding and intracellular trafficking properties.

Episodic ataxia type 1 (EA-1) is a neurological disorder arising from mutations in the Kv1.1 potassium channel alpha-subunit. EA-1 patients exhibit substantial phenotypic variability resulting from at least 14 distinct EA-1 point mutations. We found that EA-1 missense mutations generate mutant Kv1.1 subunits with folding and intracellular trafficking properties indistinguishable from wild-type Kv1.1. However, the single identified EA-1 nonsense mutation exhibits intracellular aggregation and detergent insolubility. This phenotype can be transferred to co-assembled Kv1 alpha- and Kv beta-subunits associated with Kv1.1 in neurons. These results suggest that as in many neurodegenerative disorders, intracellular aggregation of misfolded Kv1.1-containing channels may contribute to the pathophysiology of EA-1.

Animals↗
PubMed1998

Characterization of three episodic ataxia mutations in the human Kv1.1 potassium channel.

Episodic ataxia (EA) is a rare inherited neurological disorder due to mutation in the voltage-dependent Kv1.1 potassium channel. In nine unrelated families, a different missense point mutation at highly conserved positions has been reported. We have previously characterized six of the EA mutants. In this study, three recently identified mutations were introduced into the human Kv1.1 cDNA and expressed in Xenopus oocytes. Compared to wild type, T226A and T226M reduced the current amplitude by > 95%, shifted the voltage dependence by 15 mV, and slowed activation and deactivation kinetics. Currents from G311S were approximately 25% of wild type, less steeply voltage-dependent and had more pronounced C-type inactivation. These altered gating properties will reduce the delayed-rectifier potassium current which may underlie the symptoms of EA.

Animals↗
PubMed1999

Protein kinase C inhibits Kv1.1 potassium channel function.

The regulation by protein kinase C (PKC) of recombinant voltage-gated potassium (K) channels in frog oocytes was studied. Phorbol 12-myristate 13-acetate (PMA; 500 nM), an activator of PKC, caused persistent and large (up to 90%) inhibition of mouse, rat, and fly Shaker K currents. K current inhibition by PMA was blocked by inhibitors of PKC, and inhibition was not observed in control experiments with PMA analogs that do not activate PKC. However, site-directed substitution of potential PKC phosphorylation sites in the Kv1.1 protein did not prevent current inhibition by PMA. Kv1.1 current inhibition was also not accompanied by changes in macroscopic activation kinetics or in the conductance-voltage relationship. In Western blots, Kv1.1 membrane protein was not significantly reduced by PKC activation. The injection of oocytes with botulinum toxin C3 exoenzyme blocked the PMA inhibition of Kv1. 1 currents. These data are consistent with the hypothesis that PKC-mediated inhibition of Kv1.1 channel function occurs by a novel mechanism that requires a C3 exoenzyme substrate but does not alter channel activation gating or promote internalization of the channel protein.

Animals↗
PubMed2003

Glycosylation affects the protein stability and cell surface expression of Kv1.4 but Not Kv1.1 potassium channels. A pore region determinant dictates the effect of glycosylation on trafficking.

Kv1.1 and Kv1.4 potassium channels are plasma membrane glycoproteins involved in action potential repolarization. We have shown previously that glycosylation affects the gating function of Kv1.1 and that a pore region determinant of Kv1.1 and Kv1.4 affects their cell surface trafficking negatively or positively, respectively. Here we investigated the role of N-glycosylation of Kv1.1 and Kv1.4 on their protein stability, cellular localization pattern, and trafficking to the cell surface. We found that preventing N-glycosylation of Kv1.4 decreased its protein stability, induced its high partial intracellular retention, and decreased its cell surface protein levels, whereas it had little or no effect on these parameters for Kv1.1. Exchanging a trafficking pore region determinant between Kv1.1 and Kv1.4 reversed these effects of glycosylation on these chimeric channels. Thus it appeared that the Kv1.4 pore region determinant and the sugar tree attached to the S1-S2 linker showed some type of dependence in promoting proper trafficking of the protein to the cell surface, and this dependence can be transferred to chimeric Kv1.1 proteins that contain the Kv1.4 pore. Understanding the different trafficking programs of Kv1 channels, and whether they are altered by glycosylation, will highlight the different posttranslational mechanisms available to cells to modify their cell surface ion channel levels and possibly their signaling characteristics.

Animals↗
PubMed2003

Glycosylation affects rat Kv1.1 potassium channel gating by a combined surface potential and cooperative subunit interaction mechanism.

The effect of glycosylation on Kv1.l potassium channel function was investigated in mammalian cells stably transfected with Kv1.l or Kv1.1N207Q. Macroscopic current analysis showed that both channels were expressed but Kv1.1N207Q, which was not glycosylated, displayed functional differences compared with wild-type, including slowed activation kinetics, a positively shifted V 1/2, a shallower slope for the conductance versus voltage relationship, slowed C-type inactivation kinetics, and a reduced extent of and recovery from C-type inactivation. Kv1. 1N207Q activation properties were also less sensitive to divalent cations compared with those of Kv1.l. These effects were largely due to the lack of trans-Golgi added sugars, such as galactose and sialic acid, to the N207 carbohydrate tree. No apparent change in ionic current deactivation kinetics was detected inKv1.1N207Q compared with wild-type. Our data, coupled with modelling, suggested that removal of the N207 carbohydrate tree had two major effects. The first effect slowed the concerted channel transition from the last dosed state to the open state without changing the voltage dependence of its kinetics. This effect contributed to the G-V curve depolarization shift and together with the lower sensitivity to divalent cations suggested that the carbohydrate tree and its negatively charged sialic acids affected the negative surface charge density on the channel's extracellular face that was sensed by the activation gating machinery. The second effect reduced a cooperativity factor that slowed the transition from the open state to the dosed state without changing its voltage dependence. This effect accounted for the shallower G-V slope, and contributed to the depolarized G-V shift, and together with the inactivation changes it suggested that the carbohydrate tree also affected channel conformations. Thus N-glycosylation, and particularly terminal sialylation, affected Kv1.l gating properties both by altering the surface potential sensed by the channel's activation gating machinery and by modifying conformational changes regulating cooperative subunit interactions during activation and inactivation. Differences in glycosylation pattern among closely related channels may contribute to their functional differences and affect their physiological roles.

Amino Acid Sequence↗
PubMed1997

Reversible antisense inhibition of Shaker-like Kv1.1 potassium channel expression impairs associative memory in mouse and rat.

Long-term memory is thought to be subserved by functional remodeling of neuronal circuits. Changes in the weights of existing synapses in networks might depend on voltage-gated potassium currents. We therefore studied the physiological role of potassium channels in memory, concentrating on the Shaker-like Kv1.1, a late rectifying potassium channel that is highly localized within dendrites of hippocampal CA3 pyramidal and dentate gyrus granular cells. Repeated intracerebroventricular injection of antisense oligodeoxyribonucleotide to Kv1.1 reduces expression of its particular intracellular mRNA target, decreases late rectifying K+ current(s) in dentate granule cells, and impairs memory but not other motor or sensory behaviors, in two different learning paradigms, mouse passive avoidance and rat spatial memory. The latter, hippocampal-dependent memory loss occurred in the absence of long-term potentiation changes recorded both from the dentate gyrus or CA1. The specificity of the reversible antisense targeting of mRNA in adult animal brains may avoid irreversible developmental and genetic background effects that accompany transgenic "knockouts".

Animals↗
PubMed1997

An antisense oligonucleotide on the mouse Shaker-like potassium channel Kv1.1 gene prevents antinociception induced by morphine and baclofen.

Inactivation of the Kv1.1 gene, which codes for a member of the Shaker-like potassium channels by an antisense oligodeoxyribonucleotide (aODN), was carried out in mice. The effect of this inactivation on analgesia induced by morphine (5-9 mg kg-1 s.c.) and baclofen (2-5 mg kg-1 s.c.) was investigated in the mouse hot-plate test. Mice received a single intracerebroventricular injection of mKv1.1 aODN (0.5, 1.0, 2.0 or 3.0 nmol per injection), degenerated ODN or vehicle on days 1, 4 and 7. A dose-dependent inhibiton of morphine and baclofen antinociception was observed 72 h after the last intracerebroventricular aODN injection, whereas degenerated ODN and vehicle, used as controls, did not affect morphine- and baclofen-induced antinociception. Sensitivity to both analgesic drugs returned to the normal range 7 days after the end of the aODN treatment, which indicated the absence of any irreversible damage or toxicity caused by aODN. Quantitative reverse transcription-polymerase chain reaction analysis demonstrated that a decrease in mKv1.1 mRNA levels occurred only in the aODN-treated group, being absent in all control groups. Furthermore, neither aODN, degenerated ODN nor vehicle produced any behavioral impairment of mice. These results indicate that the mKv1.1 potassium channel, whose gene expression we specifically modulated by means of the antisense ODN strategy, plays an important role in central analgesia induced by morphine and baclofen.

Analgesics↗
PubMed2001

[Epileptic seizures from etomidate? The human Kv1.1 potassium channel in humans].

OBJECTIVE: It is a matter of dispute whether etomidate exhibits an epileptogenic action. It is also disputed whether frequently observed myocloni induced by etomidate are related to seizure-like activity in the EEG. The clinical effects of anaesthetic agents reflect their molecular action. A possible epileptogenic action of etomidate should, therefore, result from action on a molecular target that has yet to be identified. Suppression of Kv1.1 channels may be associated with epilepsy in men. Inhibition of Kv1.1 channels by etomidate at clinically relevant concentrations would, thus, argue in favour of an epileptogenic action of etomidate. METHODS: Patch-clamp recordings of the pharmacological action of etomidate on cloned and functionally expressed human Kv1.1 channels. RESULTS: Etomidate inhibits human Kv1.1 channels in a concentration-dependent and reversible manner. The IC50-value is 400 microM, the Hill-coefficient is 2. The ratio of free clinical plasma concentrations and the IC50-value is 0.006. At plasma concentrations determined in a clinical setting Kv1.1 channels would be suppressed by less than 0.01%. CONCLUSION: The small effect of etomidate on human Kv1.1 channels at these concentrations questions an epileptogenic action of etomidate caused by inhibition of Kv1.1 channels.

Cells, Cultured↗
PubMed2003

BTK-2, a new inhibitor of the Kv1.1 potassium channel purified from Indian scorpion Buthus tamulus.

A novel inhibitor of voltage-gated potassium channel was isolated and purified to homogeneity from the venom of the red scorpion Buthus tamulus. The primary sequence of this toxin, named BTK-2, as determined by peptide sequencing shows that it has 32 amino acid residues with six conserved cysteines. The molecular weight of the toxin was found to be 3452 Da. It was found to block the human potassium channel hKv1.1 (IC(50)=4.6 microM). BTK-2 shows 40-70% sequence similarity to the family of the short-chain toxins that specifically block potassium channels. Multiple sequence alignment helps to categorize the toxin in the ninth subfamily of the K+ channel blockers. The modeled structure of BTK-2 shows an alpha/beta scaffold similar to those of the other short scorpion toxins. Comparative analysis of the structure with those of the other toxins helps to identify the possible structure-function relationship that leads to the difference in the specificity of BTK-2 from that of the other scorpion toxins. The toxin can also be used to study the assembly of the hKv1.1 channel.

Amino Acid Sequence↗
PubMed2003

Truncation of the Shaker-like voltage-gated potassium channel, Kv1.1, causes megencephaly.

The megencephaly mouse, mceph/mceph, displays dramatically increased brain volume and hypertrophic brain cells. Despite overall enlargement, the mceph/mceph brain appears structurally normal, without oedema, hydrocephaly or leukodystrophy, and with only minor astrocytosis. Furthermore, it presents striking disturbances in expression of trophic and neuromodulating factors within the hippocampus and cortex. Using a positional cloning approach we have identified the mceph mutation. We show that mceph/mceph mice carry an 11-base-pair deletion in the gene encoding the Shaker-like voltage-gated potassium channel subtype 1, Kcna1. The mutation leads to a frame shift and the predicted MCEPH protein is truncated at amino acid 230 (out of 495), terminating with six aberrant amino acids. The expression of Kcna1 mRNA is increased in the mceph/mceph brain. However, the C-terminal domains of the corresponding Kv1.1 protein are absent. The putative MCEPH protein retains only the N-terminal domains for channel assembly and may congregate nonfunctional complexes of multiple Shaker-like subunits. Indeed, whereas Kcna2 and Kcna3 mRNA expression is normal, the mceph/mceph hippocampus displays decreased amounts of Kv1.2 and Kv1.3 proteins, suggesting interactions at the protein level. We show that mceph/mceph mice have disturbed brain electrophysiology and experience recurrent behavioural seizures, in agreement with the abnormal electrical brain activity found in Shaker mutants. However, in contrast to the commonly demonstrated epilepsy-induced neurodegeneration, we find that the mceph mutation leads to seizures with a concomitant increase in brain size, without overt neural atrophy.

Amino Acid Sequence↗
PubMed1998

Episodic ataxia mutations in Kv1.1 alter potassium channel function by dominant negative effects or haploinsufficiency.

Subunits of the voltage-gated potassium channel Kv1.1 containing mutations responsible for episodic ataxia (EA), a human inherited neurological disease, were expressed in Xenopus oocytes. Five EA subunits formed functional homomeric channels with lower current amplitudes and altered gating properties compared with wild type. Two EA mutations located in the first cytoplasmic loop, R239S and F249I, yielded minimal or no detectable current, and Western blot analysis showed reduced protein levels. Coinjection of equal amounts of EA and wild-type mRNAs, mimicking the heterozygous condition, resulted in current amplitudes and gating properties that were intermediate between wild-type and EA homomeric channels, suggesting that heteromeric channels are formed with a mixed stoichiometry of EA and wild-type subunits. To examine the relative contribution of EA subunits in forming heteromeric EA and wild-type channels, each EA subunit was made insensitive to TEA, TEA-tagged, and coexpressed with wild-type subunits. TEA-tagged R239S and F249I induced the smallest shift in TEA sensitivity compared with homomeric wild-type channels, whereas the other TEA-tagged EA subunits yielded TEA sensitivities similar to coexpression of wild-type and TEA-tagged wild-type subunits. Taken together, these results show that the different mutations in Kv1.1 affect channel function and indicate that both dominant negative effects and haplotype insufficiency may result in the symptoms of EA.

Animals↗