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Molecular Pharmacology Dec 1999Potassium channel openers (KCOs; e.g., P1075, pinacidil) exert their effects on excitable cells by opening ATP-sensitive potassium channels. These channels are...
Potassium channel openers (KCOs; e.g., P1075, pinacidil) exert their effects on excitable cells by opening ATP-sensitive potassium channels. These channels are heteromultimers composed with a 4:4 stoichiometry of an inwardly rectifying K(+) channel subunit plus a regulatory subunit comprising the receptor sites for hypoglycemic sulfonylureas and KCOs (a sulfonylurea receptor). To elucidate stoichiometry of KCO action, we analyzed P1075 sensitivity of channels coassembled from sulfonylurea receptor isoforms with high or low P1075 affinity. Concentration activation curves for cDNA ratios of 1:1 or 1:10 resembled those for channel opening resulting from interaction with a single site, whereas models for activation requiring occupation of two, three, or four sites were incongruous. We conclude KCO-induced channel activation to be mediated by interaction with a single binding site per tetradimeric complex.
Topics: ATP-Binding Cassette Transporters; Animals; Binding Sites; COS Cells; Dose-Response Relationship, Drug; Electrophysiology; Guanidines; Pinacidil; Potassium Channels; Potassium Channels, Inwardly Rectifying; Pyridines; Receptors, Drug; Recombinant Fusion Proteins; Sulfonylurea Receptors; Vasodilator Agents
PubMed: 10570067
DOI: 10.1124/mol.56.6.1370 -
The Journal of General Physiology Nov 1997The voltage-dependent potassium channel, Kv1.3, is modulated by the epidermal growth factor receptor (EGFr) and the insulin receptor tyrosine kinases. When the EGFr and...
The voltage-dependent potassium channel, Kv1.3, is modulated by the epidermal growth factor receptor (EGFr) and the insulin receptor tyrosine kinases. When the EGFr and Kv1.3 are coexpressed in HEK 293 cells, acute treatment of the cells with EGF during a patch recording can suppress the Kv1.3 current within tens of minutes. This effect appears to be due to tyrosine phosphorylation of the channel, as it is blocked by treatment with the tyrosine kinase inhibitor erbstatin, or by mutation of the tyrosine at channel amino acid position 479 to phenylalanine. Previous work has shown that there is a large increase in the tyrosine phosphorylation of Kv1.3 when it is coexpressed with the EGFr. Pretreatment of EGFr and Kv1.3 cotransfected cells with EGF before patch recording also results in a decrease in peak Kv1.3 current. Furthermore, pretreatment of cotransfected cells with an antibody to the EGFr ligand binding domain (alpha-EGFr), which blocks receptor dimerization and tyrosine kinase activation, blocks the EGFr-mediated suppression of Kv1.3 current. Insulin treatment during patch recording also causes an inhibition of Kv1.3 current after tens of minutes, while pretreatment for 18 h produces almost total suppression of current. In addition to depressing peak Kv1.3 current, EGF treatment produces a speeding of C-type inactivation, while pretreatment with the alpha-EGFr slows C-type inactivation. In contrast, insulin does not influence C-type inactivation kinetics. Mutational analysis indicates that the EGF-induced modulation of the inactivation rate occurs by a mechanism different from that of the EGF-induced decrease in peak current. Thus, receptor tyrosine kinases differentially modulate the current magnitude and kinetics of a voltage-dependent potassium channel.
Topics: Cell Line; Electric Conductivity; Epidermal Growth Factor; Humans; Kv1.3 Potassium Channel; Potassium Channels; Potassium Channels, Voltage-Gated; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor
PubMed: 9348331
DOI: 10.1085/jgp.110.5.601 -
Science's STKE : Signal Transduction... Sep 2005The potassium channel superfamily presents a rich source of targets for therapeutic intervention. Indeed, the development of specific potassium channel modulators could... (Review)
Review
The potassium channel superfamily presents a rich source of targets for therapeutic intervention. Indeed, the development of specific potassium channel modulators could lead to the effective treatment of various diseases for which current therapies are clearly suboptimal. Numerous factors play a role in determining whether the successful clinical development of such drugs can ever be achieved. However, the large body of information accumulated over the last few years on the structure and function of potassium channels is expected to drive drug-development efforts in the pharmaceutical industry on these targets, with the ultimate goal of developing therapies that will improve patient quality of life.
Topics: Animals; Drug Design; Drug Evaluation, Preclinical; Humans; Ion Channel Gating; Ion Transport; Potassium; Potassium Channel Blockers; Potassium Channels; Protein Conformation; Protein Subunits
PubMed: 16174819
DOI: 10.1126/stke.stke.3022005pe46 -
Nature Structural & Molecular Biology Oct 2004Genomic recoding by A-->I RNA editing plays an important role in diversifying the proteins involved in electrical excitability. Here, we describe editing of an...
Genomic recoding by A-->I RNA editing plays an important role in diversifying the proteins involved in electrical excitability. Here, we describe editing of an intronless potassium channel gene. A small region of human K(V)1.1 mRNA sequence directs efficient modification of one adenosine by human adenosine deaminase acting on RNA 2 (hADAR2). Mutational analysis shows that this region adopts a hairpin structure. Electrophysiological characterization reveals that the editing event (I/V) profoundly affects channel inactivation conferred by accessory beta subunits. Drosophila melanogaster Shaker channels, mimicking this editing event through mutation, exhibit a similar effect. In addition, we demonstrate that mRNAs for the paralogous D. melanogaster Shab potassium channel are edited at the same position by fly ADAR-a clear example of convergent evolution driven by adenosine deamination. These results suggest an ancient and key regulatory role for this residue in K(V) channels.
Topics: Amino Acid Sequence; Animals; Drosophila melanogaster; Humans; Kv1.1 Potassium Channel; Molecular Sequence Data; Potassium Channels; Potassium Channels, Voltage-Gated; RNA Editing; RNA, Messenger; Sequence Homology, Amino Acid
PubMed: 15361858
DOI: 10.1038/nsmb825 -
Biophysical Journal Aug 1994Inactivation of Kv3 (Kv1.3) delayed rectifier potassium channels was studied in the Xenopus oocyte expression system. These channels inactivate slowly during a long...
Inactivation of Kv3 (Kv1.3) delayed rectifier potassium channels was studied in the Xenopus oocyte expression system. These channels inactivate slowly during a long depolarizing pulse. In addition, inactivation accumulates in response to a series of short depolarizing pulses (cumulative inactivation), although no significant inactivation occurs within each short pulse. The extent of cumulative inactivation does not depend on the voltage during the depolarizing pulse, but it does vary in a biphasic manner as a function of the interpulse duration. Furthermore, the rate of cumulative inactivation is influenced by changing the rate of deactivation. These data are consistent with a model in which Kv3 channel inactivation is a state-dependent and voltage-independent process. Macroscopic and single channel experiments indicate that inactivation can occur from a closed (silent) state before channel opening. That is, channels need not open to inactivate. The transition that leads to the inactivated state from the silent state is, in fact, severalfold faster then the observed inactivation of current during long depolarizing pulses. Long pulse-induced inactivation appears to be slow, because its rate is limited by the probability that channels are in the open state, rather than in the silent state from which they can inactivate. External potassium and external calcium ions alter the rates of cumulative and long pulse-induced inactivation, suggesting that antagonistic potassium and calcium binding steps are involved in the normal gating of the channel.
Topics: Animals; Electric Stimulation; Female; Ion Channel Gating; Kinetics; Kv1.3 Potassium Channel; Mathematics; Models, Biological; Oocytes; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Time Factors; Xenopus
PubMed: 7948675
DOI: 10.1016/S0006-3495(94)80517-X -
Handbook of Experimental Pharmacology 2021Potassium channels facilitate and regulate physiological processes as diverse as electrical signaling, ion, solute and hormone secretion, fluid homeostasis, hearing,...
Potassium channels facilitate and regulate physiological processes as diverse as electrical signaling, ion, solute and hormone secretion, fluid homeostasis, hearing, pain sensation, muscular contraction, and the heartbeat. Potassium channels are each formed by either a tetramer or dimer of pore-forming α subunits that co-assemble to create a multimer with a K-selective pore that in most cases is capable of functioning as a discrete unit to pass K ions across the cell membrane. The reality in vivo, however, is that the potassium channel α subunit multimers co-assemble with ancillary subunits to serve specific physiological functions. The ancillary subunits impart specific physiological properties that are often required for a particular activity in vivo; in addition, ancillary subunit interaction often alters the pharmacology of the resultant complex. In this chapter the modes of action of ancillary subunits on K channel physiology and pharmacology are described and categorized into various mechanistic classes.
Topics: Potassium Channels; Potassium Channels, Voltage-Gated
PubMed: 34247280
DOI: 10.1007/164_2021_512 -
Pharmacology & Therapeutics Apr 2001KCNQ genes encode a growing family of six transmembrane domains, single pore-loop, K(+) channel alpha-subunits that have a wide range of physiological correlates. KCNQ1... (Review)
Review
KCNQ genes encode a growing family of six transmembrane domains, single pore-loop, K(+) channel alpha-subunits that have a wide range of physiological correlates. KCNQ1 (KvLTQ1) is co-assembled with the product of the KCNE1 (minimal K(+)-channel protein) gene in the heart to form a cardiac-delayed rectifier-like K(+) current. Mutations in this channel can cause one form of inherited long QT syndrome (LQT1), as well as being associated with a form of deafness. KCNQ1 can also co-assemble with KCNE3, and may be the molecular correlate of the cyclic AMP-regulated K(+) current present in colonic crypt cells. KCNQ2 and KCNQ3 heteromultimers are thought to underlie the M-current; mutations in these genes may cause an inherited form of juvenile epilepsy. The KCNQ4 gene is thought to encode the molecular correlate of the I(K,n) in outer hair cells of the cochlea and I(K,L) in Type I hair cells of the vestibular apparatus, mutations in which lead to a form of inherited deafness. The recently identified KCNQ5 gene is expressed in brain and skeletal muscle, and can co-assemble with KCNQ3, suggesting it may also play a role in the M-current heterogeneity. This review will set this family of K(+) channels amongst the other known families. It will highlight the genes, physiology, pharmacology, and pathophysiology of this recently discovered, but important, family of K(+) channels.
Topics: Animals; Colon; Deafness; Electrochemistry; Epilepsy; Humans; KCNQ Potassium Channels; KCNQ1 Potassium Channel; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Long QT Syndrome; Models, Molecular; Mutation; Myocardium; Potassium Channels; Potassium Channels, Voltage-Gated
PubMed: 11448722
DOI: 10.1016/s0163-7258(01)00116-4 -
Postepy Biochemii 2016In the inner mitochondrial membrane several potassium channels have been identified whose activation lead to cytoprotection during ischemic event. It was found that... (Review)
Review
In the inner mitochondrial membrane several potassium channels have been identified whose activation lead to cytoprotection during ischemic event. It was found that activation of mitochondrial large conductance calcium activated potassium channel (mitoBK) and ATP regulated potassium channel (mitoK) preserves brain and heart muscle cells against ischemia/reperfusion induced damage. However the detailed cytoprotection mechanism remains unclear. Similarly, the molecular structures and protein interactions of the mitochondrial potassium channels are still unknown. In this article, we summarize the current knowledge of the mitoK and mitoBK channels topology. Different aspects of this topic are discussed like import and assembly of the channel subunits and biophysical properties of mitochondrial compartments. Additionally, the consequences of different topology models on the cytoprotective function of the mitochondrial potassium channels were analyzed.
Topics: Animals; Humans; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Mitochondria; Mitochondrial Proteins; Potassium Channels; Protein Conformation; Protein Multimerization; Protein Transport
PubMed: 28132472
DOI: No ID Found -
The Journal of Biological Chemistry Feb 2004High frequency firing in mammalian neurons requires ultra-rapid delayed rectifier potassium currents generated by homomeric or heteromeric assemblies of Kv3.1 and Kv3.2...
High frequency firing in mammalian neurons requires ultra-rapid delayed rectifier potassium currents generated by homomeric or heteromeric assemblies of Kv3.1 and Kv3.2 potassium channel alpha subunits. Kv3.1 alpha subunits can also form slower activating channels by coassembling with MinK-related peptide 2 (MiRP2), a single transmembrane domain potassium channel ancillary subunit. Here, using channel subunits cloned from rat and expressed in Chinese hamster ovary cells, we show that modulation by MinK, MiRP1, and MiRP2 is a general mechanism for slowing of Kv3.1 and Kv3.2 channel activation and deactivation and acceleration of inactivation, creating a functionally diverse range of channel complexes. MiRP1 also negatively shifts the voltage dependence of Kv3.1 and Kv3.2 channel activation. Furthermore, MinK, MiRP1, and MiRP2 each form channels with Kv3.1-Kv3.2 heteromers that are kinetically distinct from one another and from MiRP/homomeric Kv3 channels. The findings illustrate a mechanism for dynamic expansion of the functional repertoire of Kv3.1 and Kv3.2 potassium currents and suggest roles for these alpha subunits outside the scope of sustained rapid neuronal firing.
Topics: Animals; CHO Cells; Cricetinae; Electric Conductivity; Electrophysiology; Humans; Nerve Tissue Proteins; Neuropeptides; Potassium Channels; Potassium Channels, Voltage-Gated; Rats; Recombinant Proteins; Shaker Superfamily of Potassium Channels; Shaw Potassium Channels; Structure-Activity Relationship; Transfection
PubMed: 14679187
DOI: 10.1074/jbc.M310501200 -
Brain Research May 1996The action of the epileptogenic agent pentylenetetrazol (PTZ) on a cloned potassium channel of the rat brain was studied. The Kv1.1 channel was expressed in oocytes of...
The action of the epileptogenic agent pentylenetetrazol (PTZ) on a cloned potassium channel of the rat brain was studied. The Kv1.1 channel was expressed in oocytes of Xenopus laevis and potassium currents were investigated in outside-out and inside-out membrane patches. The results show that PTZ increased the multi-channel potassium currents at strongly negative potentials and decreased them at potentials positive to -35 mV both in outside-out and inside-out membrane patches. The extent and manner of PTZ action, the concentration dependence as well as the onset and time course of the PTZ effect were the same both in outside-out and inside-out membrane patches. The single-channel potassium currents showed an increase in open probability and frequency of opening and a decrease in close time at -50 mV and vice versa at 0 mV with application of PTZ. The amplitude of single-channel current, the open time and the latency to the first channel opening remained almost unchanged under PTZ. The results indicate that PTZ acts via the cell membrane and influences the membrane-associated part of the potassium channel. Thereby, PTZ accelerates the transition from the inactivated to the open state of the channel at strongly negative potentials and reduces it at slightly negative and positive potentials. This mechanism may be the basis for a gate function which is in favour of the development of epileptic discharges.
Topics: Animals; Cloning, Molecular; Convulsants; Electric Conductivity; Female; Neurons; Oocytes; Pentylenetetrazole; Potassium Channels; Rats; Xenopus laevis
PubMed: 8813350
DOI: 10.1016/0006-8993(96)00181-3