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Results for “Kv1.2 Potassium Channel”

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PubMed1999

Sensory activity affects sensory axon development in C. elegans.

The simple nervous system of the nematode C. elegans consists of 302 neurons with highly reproducible morphologies, suggesting a hard-wired program of axon guidance. Surprisingly, we show here that sensory activity shapes sensory axon morphology in C. elegans. A class of mutants with deformed sensory cilia at their dendrite endings have extra axon branches, suggesting that sensory deprivation disrupts axon outgrowth. Mutations that alter calcium channels or membrane potential cause similar defects. Cell-specific perturbations of sensory activity can cause cell-autonomous changes in axon morphology. Although the sensory axons initially reach their targets in the embryo, the mutations that alter sensory activity cause extra axon growth late in development. Thus, perturbations of activity affect the maintenance of sensory axon morphology after an initial pattern of innervation is established. This system provides a genetically tractable model for identifying molecular mechanisms linking neuronal activity to nervous system structure.

Animals↗

PubMed1999

Pharmacological properties of trimebutine and N-monodesmethyltrimebutine.

Trimebutine [2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxybenzoate hydrogen maleate (TMB)] has been demonstrated to be active for relieving abdominal pain in humans. To better understand its mechanism of action, we have tested TMB; nor-TMB, its main metabolite in humans; and their respective stereoisomers for their affinity toward sodium channels labeled by [3H]batrachotoxin, their effect on sodium, potassium, and calcium currents in rat dorsal root ganglia neurons, and their effect on veratridine-induced glutamate release from rat spinal cord slices. TMB has also been tested in an animal model of local anesthesia. TMB (Ki = 2.66 +/- 0.15 microM) and nor-TMB (Ki = 0.73 +/- 0.02 microM) displaced [3H]batrachotoxin from its binding site with affinities similar to that of bupivacaine (Ki = 7.1 +/- 0.9 microM). nor-TMB was found to block veratridine-induced glutamate release with an IC50 value of 8.5 microM, which is very similar to that of bupivacaine (IC50 = 8.2 microM); the effect of TMB was limited to 50% inhibition at 100 microM. TMB and nor-TMB blocked sodium currents in sensory neurons from rat dorsal root ganglia (IC50 = 0.83 +/- 0.09 and 1.23 +/- 0.19 microM, respectively), whereas no effect was observed on calcium currents at the same concentrations. A limited effect was observed on potassium currents (IC50 = 23 +/- 6 at 10 microM) for TMB. In vivo, when tested in the rabbit corneal reflex, TMB displayed a local anesthetic activity 17-fold more potent than that of lidocaine.

Animals↗

PubMed1999

Xenopus embryonic spinal neurons express potassium channel Kvbeta subunits.

Developmental regulation of voltage-dependent delayed rectifier potassium current (I(Kv)) of Xenopus primary spinal neurons regulates the waveform of the action potential. I(Kv) undergoes a tripling in density and acceleration of it activation kinetics during the initial day of its appearance. Another voltage-dependent potassium current, the A current, is acquired during the subsequent day and contributes to further shortening of the impulse duration. To decipher the molecular mechanisms underlying this functional differentiation, we are identifying potassium channel genes expressed in the embryonic amphibian nervous system. Potassium channels consist of pore-forming (alpha) as well as auxiliary (beta) subunits. Here, we report the primary sequence, developmental localization, and functional properties of two Xenopus Kvbeta genes. On the basis of primary sequence, one of these (xKvbeta2) is highly conserved with Kvbeta2 genes identified in other species, whereas the other (xKvbeta4) appears to identify a new member of the Kvbeta family. Both are expressed in developing spinal neurons during the period of impulse maturation but in different neuronal populations. In a heterologous system, coexpression of xKvbeta subunits modulates properties of potassium current that are developmentally regulated in the endogenous I(Kv). Consistent with xKvbeta4's unique primary sequence, the repertoire of functional effects it has on coexpressed Kv1alpha subunits is novel. Taken together, the results implicate auxiliary subunits in regulation of potassium current function and action potential waveforms in subpopulations of embryonic primary spinal neurons.

Amino Acid Sequence↗

PubMed2000

Electrophysiological characterization of voltage-gated K(+) currents in cerebellar basket and purkinje cells: Kv1 and Kv3 channel subfamilies are present in basket cell nerve terminals.

To understand the processes underlying fast synaptic transmission in the mammalian CNS, we must have detailed knowledge of the identity, location, and physiology of the ion channels in the neuronal membrane. From labeling studies we can get clues regarding the distribution of ion channels, but electrophysiological methods are required to determine the importance of each ion channel in CNS transmission. Dendrotoxin-sensitive potassium channel subunits are highly concentrated in cerebellar basket cell nerve terminals, and we have previously shown that they are responsible for a significant fraction of the voltage-gated potassium current in this region. Here, we further investigate the characteristics and pharmacology of the voltage-dependent potassium currents in these inhibitory nerve terminals and compare these observations with those obtained from somatic recordings in basket and Purkinje cell soma regions. We find that alpha-DTX blocks basket cell nerve terminal currents and not somatic currents, and the IC(50) for alpha-DTX in basket cell terminals is 3.2 nM. There are at least two distinct types of potassium currents in the nerve terminal, a DTX-sensitive low-threshold component, and a second component that activates at much more positive voltages. Pharmacological experiments also reveal that nerve terminal potassium currents are also markedly reduced by 4-AP and TEA, with both high-sensitivity (micromolar) and low-sensitivity (millimolar) components present. We suggest that basket cell nerve terminals have potassium channels from both the Kv1 and Kv3 subfamilies, whereas somatic currents in basket cell and Purkinje cell bodies are more homogeneous.

4-Aminopyridine↗

PubMed2003

Paranodal interactions regulate expression of sodium channel subtypes and provide a diffusion barrier for the node of Ranvier.

The node of Ranvier is a distinct domain of myelinated axons that is highly enriched in sodium channels and is critical for impulse propagation. During development, the channel subtypes expressed at the node undergo a transition from Nav1.2 to Nav1.6. Specialized junctions that form between the paranodal glial membranes and axon flank the nodes and are candidates to regulate their maturation and delineate their boundaries. To investigate these roles, we characterized node development in mice deficient in contactin-associated protein (Caspr), an integral junctional component. Paranodes in these mice lack transverse bands, a hallmark of the mature junction, and exhibit progressive disruption of axon-paranodal loop interactions in the CNS. Caspr mutant mice display significant abnormalities at central nodes; components of the nodes progressively disperse along axons, and many nodes fail to mature properly, persistently expressing Nav1.2 rather than Nav1.6. In contrast, PNS nodes are only modestly longer and, although maturation is delayed, eventually all express Nav1.6. Potassium channels are aberrantly clustered in the paranodes; these clusters are lost over time in the CNS, whereas they persist in the PNS. These findings indicate that interactions of the paranodal loops with the axon promote the transition in sodium channel subtypes at CNS nodes and provide a lateral diffusion barrier that, even in the absence of transverse bands, maintains a high concentration of components at the node and the integrity of voltage-gated channel domains.

Age Factors↗

PubMed1996

Homogeneous development of electrical excitability via heterogeneous ion channel expression.

Synchronous differentiation of delayed-rectifier potassium current regulates electrical excitability and calcium entry in motor, sensory, and interneurons of the developing amphibian spinal cord. Although Kv1 and Kv2 potassium channel transcripts are detectable in these cells, it is not known which transcript contributes to functional expression. Overexpression of a Kv1 dominant-negative subunit indicates that 20% of neurons have only Kv1 potassium currents. In other neurons, non-Kv1 channels function because the dominant-negative subunit either only partially suppresses or has no effect on current. Thus, diverse embryonic neurons coordinate differentiation of excitability yet rely on heterogeneous potassium channel gene expression.

Animals↗

PubMed1999

Mapping the functional anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3. Clues to design analogs with enhanced selectivity.

BgK is a peptide from the sea anemone Bunodosoma granulifera, which blocks Kv1.1, Kv1.2, and Kv1.3 potassium channels. Using 25 analogs substituted at a single position by an alanine residue, we performed the complete mapping of the BgK binding sites for the three Kv1 channels. These binding sites included three common residues (Ser-23, Lys-25, and Tyr-26) and a variable set of additional residues depending on the particular channel. Shortening the side chain of Lys-25 by taking out the four methylene groups dramatically decreased the BgK affinity to all Kv1 channels tested. However, the analog K25Orn displayed increased potency on Kv1.2, which makes this peptide a selective blocker for Kv1.2 (K(D) 50- and 300-fold lower than for Kv1.1 and Kv1.3, respectively). BgK analogs with enhanced selectivity could also be made by substituting residues that are differentially involved in the binding to some of the three Kv1 channels. For example, the analog F6A was found to be >500-fold more potent for Kv1.1 than for Kv1.2 and Kv1.3. These results provide new information about the mechanisms by which a channel blocker distinguishes individual channels among closely related isoforms and give clues for designing analogs with enhanced selectivity.

Amino Acid Substitution↗

PubMed2002

Brownian dynamics simulations of the recognition of the scorpion toxin maurotoxin with the voltage-gated potassium ion channels.

The recognition of the scorpion toxin maurotoxin (MTX) by the voltage-gated potassium (Kv1) channels, Kv1.1, Kv1.2, and Kv1.3, has been studied by means of Brownian dynamics (BD) simulations. All of the 35 available structures of MTX in the Protein Data Bank (http://www.rcsb.org/pdb) determined by nuclear magnetic resonance were considered during the simulations, which indicated that the conformation of MTX significantly affected both the recognition and the binding between MTX and the Kv1 channels. Comparing the top five highest-frequency structures of MTX binding to the Kv1 channels, we found that the Kv1.2 channel, with the highest docking frequencies and the lowest electrostatic interaction energies, was the most favorable for MTX binding, whereas Kv1.1 was intermediate, and Kv1.3 was the least favorable one. Among the 35 structures of MTX, the 10th structure docked into the binding site of the Kv1.2 channel with the highest probability and the most favorable electrostatic interactions. From the MTX-Kv1.2 binding model, we identified the critical residues for the recognition of these two proteins through triplet contact analyses. MTX locates around the extracellular mouth of the Kv1 channels, making contacts with its beta-sheets. Lys23, a conserved amino acid in the scorpion toxins, protrudes into the pore of the Kv1.2 channel and forms two hydrogen bonds with the conserved residues Gly401(D) and Tyr400(C) and one hydrophobic contact with Gly401(C) of the Kv1.2 channel. The critical triplet contacts for recognition between MTX and the Kv1.2 channel are Lys23(MTX)-Asp402(C)(Kv1), Lys27(MTX)-Asp378(D)(Kv1), and Lys30(MTX)-Asp402(A)(Kv1). In addition, six hydrogen-bonding interactions are formed between residues Lys23, Lys27, Lys30, and Tyr32 of MTX and residues Gly401, Tyr400, Asp402, Asp378, and Thr406 of Kv1.2. Many of them are formed by side chains of residues of MTX and backbone atoms of the Kv1.2 channel. Five hydrophobic contacts exist between residues Pro20, Lys23, Lys30 and Tyr32 of MTX and residues Asp402, Val404, Gly401, and Arg377 of the Kv1.2 channel. The simulation results are in agreement with the previous molecular biology experiments and explain the binding phenomena between MTX and Kv1 channels at the molecular level. The consistency between the results of the BD simulations and the experimental data indicated that our three-dimensional model of the MTX-Kv1.2 channel complex is reasonable and can be used in additional biological studies, such as rational design of novel therapeutic agents blocking the voltage-gated channels and in mutagenesis studies in both the toxins and the Kv1 channels. In particular, both the BD simulations and the molecular mechanics refinements indicate that residue Asp378 of the Kv1.2 channel is critical for its recognition and binding functionality toward MTX. This phenomenon has not been appreciated in the previous mutagenesis experiments, indicating this might be a new clue for additional functional study of Kv1 channels.

Amino Acid Motifs↗

PubMed2006

Dynamics of K+ ion conduction through Kv1.2.

The crystallographic structure of a potassium channel, Kv1.2, in an open state makes it feasible to simulate entire K(+) ion permeation events driven by a voltage bias and, thereby, elucidate the mechanism underlying ion conduction and selectivity of this type of channel. This Letter demonstrates that molecular dynamics simulations can provide movies of the overall conduction of K(+) ions through Kv1.2. As suggested earlier, the conduction is concerted in the selectivity filter, involving 2-3 ions residing mainly at sites identified previously by crystallography and modeling. The simulations reveal, however, the jumps of ions between these sites and identify the sequence of multi-ion configurations involved in permeation.

Computer Simulation↗

PubMedDate not supplied

Molecular and cellular mechanisms of neuroprotection by vascular endothelial growth factor.

The present view of the neuroprotective functions and mechanisms of action of vascular endothelial growth factor (VEGF) is based on studies of neuronal ischemic/hypoxic models in vivo and in vitro. Endogenous neuronal VEGF increases in the ischemic brain and plays a neuroprotective role in the pathophysiologic processes that follow stroke. Exogenous VEGF, directly administered or overexpressed by gene delivery into rat brains, reduces ischemic brain infarct and decreases hypoxic neuronal death. The main neuroprotective mechanisms of VEGF include: (1) modulation of the phosphatidylinositol 3'-kinase (PI3K)/Akt/nuclear factor-kappaB signaling pathway, inhibition of caspase-3 activity, and reduction of ischemic neuronal apoptosis; (2) inhibition of outward delayed rectifier potassium channel currents and increase of ischemia-induced tyrosine phosphorylation of Kv1.2 potassium channel proteins via activation of the PI3K pathway; and (3) enhancement of proliferation and migration of neural progenitors in the subventricular zone and improvement of striatal neurogenesis and maturation of newborn neurons in adult rat brains after stroke.

Animals↗

PubMed1997

The m1 muscarinic acetylcholine receptor transactivates the EGF receptor to modulate ion channel activity.

Intracellular tyrosine kinases link the G protein-coupled m1 muscarinic acetylcholine receptor (mAChR) to multiple cellular responses. However, the mechanisms by which m1 mAChRs stimulate tyrosine kinase activity and the identity of the kinases within particular signaling pathways remain largely unknown. We show that the epidermal growth factor receptor (EGFR), a single transmembrane receptor tyrosine kinase, becomes catalytically active and dimerized through an m1 mAChR-regulated pathway that requires protein kinase C, but is independent of EGF. Finally, we demonstrate that transactivation of the EGFR plays a major role in a pathway linking m1 mAChRs to modulation of the Kv1.2 potassium channel. These results demonstrate a ligand-independent mechanism of EGFR transactivation by m1 mAChRs and reveal a novel role for these growth factor receptors in the regulation of ion channels by G protein-coupled receptors.

Carbachol↗

PubMed1996

Novel effects of dendrotoxin homologues on subtypes of mammalian Kv1 potassium channels expressed in Xenopus oocytes.

We have examined the effects of two DTX homologues, toxin I and toxin K, on Kv1.1, Kv1.2 and Kv1.6 channels expressed in Xenopus oocytes. Toxin I blocked all three channels; in contrast, toxin K was selective for Kv1.1. Both toxins slowed channel activation and inactivation kinetics with 10 nM toxin I approximately doubling activation and inactivation time constants of Kv1.1. For the first time, we have demonstrated the selectivity of a DTX homologue for a single cloned Kv1 channel and suggest that these toxins may sterically hinder the conformational changes that occur during channel gating.

Animals↗

PubMed2004

Identification of a mammalian target of kappaM-conotoxin RIIIK.

Despite the great variability of the conus peptides characterized until now only relatively few have been identified that interact with K+ channels. kappaM-conotoxin RIIIK (kappaM-RIIIK) is a 24 amino acid peptide from Conus radiatus, which is structurally similar to micro-conotoxin GIIIA, a peptide known to block specifically skeletal muscle Na+ channels. Recently, it has been shown that kappaM-RIIIK does not interact with Na) channels, but inhibits Shaker potassium channels expressed in Xenopus oocytes. It was demonstrated that kappaM-RIIIK binds to the pore region of Shaker channels and a teleost homologue of the Shaker channel TSha1 was identified as a high affinity target of the toxin. In contrast the mammalian Shaker-homologues Kv1.1, Kv1.3, Kv1.4 are not affected by the toxin. In this study the activity of kappaM-RIIIK on other mammalian Kv1 K+ channels expressed in Xenopus oocytes was investigated. We demonstrate that kappaM-conotoxin RIIIK up to 5 microM exhibits no significant effect on Kv1.5 and Kv1.6 mediated currents, but the human Kv1.2 K+ channel is blocked by this peptide. The binding of kappaM-RIIIK to Kv1.2 channels is state dependent with an IC50 for the closed state of about 200 nM and for the open state of about 400 nM at a test potential of 0 mV. kappaM-conotoxin RIIIK is the first conotoxin described to block human Kv1.2 potassium channels.

Animals↗

PubMed2000

Role of receptor protein tyrosine phosphatase alpha (RPTPalpha) and tyrosine phosphorylation in the serotonergic inhibition of voltage-dependent potassium channels.

The activity of voltage-gated potassium (Kv) channels can be dynamically modulated by several events, including neurotransmitter-stimulated biochemical cascades mediated by G-protein-coupled receptors. By using a heterologous expression system, we show that activating the 5-HT2C receptor inhibits both Kv1.1 and Kv1.2 channels through a tyrosine phosphorylation mechanism. The major molecular determinants of channel inhibition were identified as two tyrosine residues located in the N-terminal region of the Kv channel subunit. Furthermore, we demonstrate that receptor protein tyrosine phosphatase alpha (RPTPalpha), a receptor protein tyrosine phosphatase, co-ordinates the inhibition process mediated via 5-HT2C receptors. We therefore propose that the serotonergic regulation of human Kv1.1 and Kv1.2 channel activity by the 5-HT2C receptor involves the dual coordination of both RPTPalpha and specific tyrosine kinases coupled to this receptor.

Animals↗

PubMed1999

Differential sensitivity of voltage-gated potassium channels Kv1.5 and Kv1.2 to acidic pH and molecular identification of pH sensor.

Kv1.2 and Kv1.5 are two subtypes of voltage-gated potassium channels expressed in heart that are thought to contribute to phase 1 (ITO) and phase 3 (IK) components of cardiac action potential repolarization. Although the effect of decreased pH in prolonging cardiac action potentials is well documented, the molecular target of acidification has not previously been determined. We expressed Kv1.2 and Kv1.5 in Xenopus oocytes to study the effect of acidic and alkaline extracellular pH on channel function. Using two-electrode voltage clamp and cellattached patch clamp, we demonstrate that Kv1. 5 channels show enhanced C-type inactivation at acidic pH that is relevant to pathophysiological conditions. In contrast, homologous Kv1.2 channels are resistant to acidic pH. Both channel types are insensitive to alkaline pH. A histidine residue in the third extracellular loop of Kv1.5 (H452) accounts for the difference in pH sensitivity between the Kv1.5 and Kv1.2 channels. Mutation of histidine H452 to a glutamine residue in Kv1.5 yields a channel that no longer shows enhanced inactivation with acidification. These data provide insight into mechanisms subserving known pH effects on cellular signaling functions. Our results demonstrate that H452 in the third extracellular loop of Kv1.5 plays a role in C-type inactivation, thus expanding the known complement of protein regions that contribute to the slow K+ channel inactivation mechanism.

Amino Acid Sequence↗

PubMed2001

A discrete amino terminal domain of Kv1.5 and Kv1.4 potassium channels interacts with the spectrin repeats of alpha-actinin-2.

The interaction between the amino terminus of Kv1-type potassium channels and alpha-actinin-2 has been investigated. Using a combination of yeast two-hybrid analysis and in vitro binding assays, alpha-actinin-2 was found to bind to the N-termini of both Kv1.4 and Kv1.5 but not to the equivalent segments of Kv1.1, Kv1.2 or Kv1.3. Deletion analysis in the in vitro binding assays delineated the actinin binding region of Kv1.5 to between amino acids 73 and 148 of the channel. The Kv1.5 binding sites in alpha-actinin-2 were found to lie within actinin's internal spectrin repeats. Unlike the reported interaction between actinin and the NMDA receptor, calmodulin was found to have no effect on actinin binding to Kv1.5.

Actinin↗

PubMed2002

Characteristics of brain Kv1 channels tailored to mimic native counterparts by tandem linkage of alpha subunits: implications for K+ channelopathies.

Most neuronal Kv1 channels contain Kv1.1, Kv1.2 alpha, and Kvbeta2.1 subunits, yet the influences of their stoichiometries on properties of the (alpha)(4)(beta)(4) variants remain undefined. cDNAs were engineered to contain 0, 1, 2, or 4 copies of Kv1.1 with the requisite number of Kv1.2 and co-expressed in mammalian cells with Kvbeta2.1 to achieve "native-like" hetero-oligomers. The monomeric (Kv1.1 or 1.2), dimeric (Kv1.1-1.2 or 1.2-1.2), and tetrameric (Kv1.1-(1.2)(3)) constructs produced proteins of M(r) approximately 62,000, 120,000, and 240,000, which assembled into (alpha)(4)(beta)(4) complexes. Each alpha cRNA yielded a distinct K(+) current in oocytes, with voltage dependence of activation being shifted negatively as the Kv1.1 content in tetramers was increased. Channels containing 1, 2, or 4 copies of Kv1.1 were blocked by dendrotoxin k (DTX)(k) with similarly high potencies, whereas Kv(1.2)(4) proved nonsusceptible. Accordingly, Kv1.2/beta2.1 expressed in baby hamster kidney cells failed to bind DTX(k); in contrast, oligomers containing only one Kv1.1 subunit in a tetramer exhibited high affinity, with additional copies causing modest increases. Thus, one Kv1.1 subunit largely confers high affinity for DTX(k), whereas channel electrophysiological properties are tailored by the content of Kv1.1 relative to Kv1.2. This notable advance could explain the diversity of symptoms of human episodic ataxia I, which is often accompanied by myokymia, due to mutated Kv1.1 being assembled in different combinations with wild-type and Kv1.2.

Animals↗

PubMed2004

Decreased expression of voltage-gated K+ channels in pulmonary artery smooth muscles cells in nitrofen-induced congenital diaphragmatic hernia in rats.

The newborn with congenital diaphragmatic hernia (CDH) is at high risk of developing persistent pulmonary hypertension (PPH). Recently, smooth muscle K(+) channels have been implicated in hypoxic pulmonary vasoconstriction in adults. We hypothesized that the hyperreactivity of the newborn pulmonary vasculature in CDH might reflect a relatively low level of smooth muscle K(+) channel activity because of hypoxemia, which could give rise to excessive smooth muscle cell depolarisation and lead to failure of the pulmonary vasculature to adapt to extrauterine life. We therefore investigated K(+) channel subunits in pulmonary artery smooth muscle cells (PASMC) in the nitrofen-induced CDH lung in rats. The CDH model was induced in pregnant rats after administration of 100 mg nitrofen on day 9.5 of gestation (term = 22 days). Dexamethasone (0.25 mg/kg) was given on days 18.5 and 19.5 of gestation. Cesarean section was performed on day 21. Fetuses were divided into three groups: group I, normal control; group II, nitrofen-induced CDH; and group III, nitrofen-induced CDH with antenatal dexamethasone treatment. Reverse transcription polymerase chain reaction (RT-PCR) was performed to evaluate the relative amount of the potassium channels Kv1.2, Kv2.1, and KvCa mRNA. Indirect immunohistochemistry was performed using a laser scanning confocal microscope with anti-Kv1.2, -Kv2.1, and -KvCa antibodies. In the CDH lung, Kv1.2, Kv2.1, and KvCa immunoreactivity was markedly decreased in PASMC compared with controls. Relative mRNA levels of potassium channel anti-Kv1.2, -Kv2.1, and -KvCa were significantly decreased in the CDH lung compared with controls (p<0.05). Dexamethasone treatment increased Kv1.2, Kv2.1, and KvCa immunoreactivity and mRNA levels in the CDH lung. Changes in voltage-gate K(+) channel subunits expression in the CDH lung suggest that potassium channels may play an important role in the development of pulmonary hypertension. Antenatal dexamethasone may modulate pulmonary vascular tone in the CDH hypoplastic lung by selectively upregulating local expression of Kv1.2, Kv2.1, and KvCa.

Analysis of Variance↗