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Biochimica Et Biophysica Acta 2006Mitochondrial potassium channels, such as ATP-regulated or large conductance Ca2+ -activated and voltage gated channels were implicated in cytoprotective phenomenon in... (Review)
Review
Mitochondrial potassium channels, such as ATP-regulated or large conductance Ca2+ -activated and voltage gated channels were implicated in cytoprotective phenomenon in different tissues. Basic effects of these channels activity include changes in mitochondrial matrix volume, mitochondrial respiration and membrane potential, and generation of reactive oxygen species. In this paper, we describe the pharmacological properties of mitochondrial potassium channels and their modulation by channel inhibitors and potassium channel openers. We also discuss potential side effects of these substances.
Topics: Adenosine Triphosphate; Animals; Calcium; Humans; Ion Channel Gating; Membrane Potentials; Mitochondria; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Calcium-Activated; Potassium Channels, Voltage-Gated
PubMed: 16787636
DOI: 10.1016/j.bbabio.2006.05.002 -
Biomolecules Sep 2020Pulmonary arterial hypertension (PAH) is a rare and severe cardiopulmonary disease without curative treatments. PAH is a multifactorial disease that involves genetic... (Review)
Review
Pulmonary arterial hypertension (PAH) is a rare and severe cardiopulmonary disease without curative treatments. PAH is a multifactorial disease that involves genetic predisposition, epigenetic factors, and environmental factors (drugs, toxins, viruses, hypoxia, and inflammation), which contribute to the initiation or development of irreversible remodeling of the pulmonary vessels. The recent identification of loss-of-function mutations in (KCNK3 or TASK-1) and (SUR1), or gain-of-function mutations in (SUR2), as well as polymorphisms in (Kv1.5), which encode two potassium (K) channels and two K channel regulatory subunits, has revived the interest of ion channels in PAH. This review focuses on KCNK3, SUR1, SUR2, and Kv1.5 channels in pulmonary vasculature and discusses their pathophysiological contribution to and therapeutic potential in PAH.
Topics: Animals; Drug Delivery Systems; Humans; Kv1.5 Potassium Channel; Nerve Tissue Proteins; Potassium Channels; Potassium Channels, Inwardly Rectifying; Potassium Channels, Tandem Pore Domain; Pulmonary Arterial Hypertension; Sulfonylurea Receptors
PubMed: 32882918
DOI: 10.3390/biom10091261 -
The Journal of Physiological Sciences :... Nov 2019The mechanism underlying ion permeation through potassium channels still remains controversial. K ions permeate across a narrow selectivity filter (SF) in a single file....
The mechanism underlying ion permeation through potassium channels still remains controversial. K ions permeate across a narrow selectivity filter (SF) in a single file. Conventional scenarios assume that K ions are tightly bound in the SF, and, thus, they are displaced from their energy well by ion-ion repulsion with an incoming ion. This tight coupling between entering and exiting ions has been called the "knock-on" mechanism. However, this paradigm is contradicted by experimental data measuring the water-ion flux coupling ratio, demonstrating fewer ion occupancies. Here, the results of molecular dynamics simulations of permeation through the KcsA potassium channel revealed an alternative mechanism. In the aligned ions in the SF (an ion queue), the outermost K was readily and spontaneously released toward the extracellular space, and the affinity of the relevant ion was ~ 50 mM. Based on this low-affinity regime, a simple queueing mechanism described by loose coupling of entering and exiting ions is proposed.
Topics: Bacterial Proteins; Models, Chemical; Molecular Dynamics Simulation; Potassium; Potassium Channels
PubMed: 31456113
DOI: 10.1007/s12576-019-00706-4 -
The Journal of Investigative Dermatology Jul 1993The opening of intracellular potassium channels is a common mechanism of action for a set of anti-hypertensive drugs that includes the hair-growth-inducing agent... (Review)
Review
The opening of intracellular potassium channels is a common mechanism of action for a set of anti-hypertensive drugs that includes the hair-growth-inducing agent minoxidil. Recent work suggests potassium channel openers (PCOs) also influence hair growth. Correlative studies demonstrate that a series of PCOs including minoxidil, pinacidil, P-1075, an active pinacidil analog, RP-49,356, cromakalim, and nicorandil maintain hair growth in cultured vibrissa follicles. Studies using balding stumptail macaques verify that minoxidil, P-1075, and cromakalim but not RP-49,356 stimulate hair growth. The definition of potassium channels and documentation of drug effects on these channels is classically done using electrophysiologic techniques. Such studies require the identification and isolation of target cells. Both these are among the unsolved problems in the area of hair biology. Estimating K+ flux using 86Rb+ as a K+ tracer is an accepted method of assessing potassium channel conductance in other organ systems. Both pinacidil and RP-49,356 induce measurable Rb+ flux in isolated vibrissa follicles and a hair epithelial cell line whereas neither minoxidil nor minoxidil sulfate had measurable effects. Potassium channels have been studied successfully in other organ systems using specific pharmacologic blockers for the various channel subtypes. Blockers including glyburide, tetraethylammonium, and procaine failed to inhibit minoxidil stimulation of cultured follicles. The current explosion of knowledge on potassium channel biology, cloning of channels, and continued progress in hair biology promise to clarify the role of K+ ions in the control of hair follicles.
Topics: Hair; Humans; Potassium Channels
PubMed: 8326149
DOI: 10.1111/1523-1747.ep12363290 -
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 -
Journal of Molecular Biology Nov 2021Regulation of ion conduction through the pore of a K channel takes place through the coordinated action of the activation gate at the bundle crossing of the inner...
Regulation of ion conduction through the pore of a K channel takes place through the coordinated action of the activation gate at the bundle crossing of the inner helices and the inactivation gate located at the selectivity filter. The mechanism of allosteric coupling of these gates is of key interest. Here we report new insights into this allosteric coupling mechanism from studies on a W67F mutant of the KcsA channel. W67 is in the pore helix and is highly conserved in K channels. The KcsA W67F channel shows severely reduced inactivation and an enhanced rate of activation. We use continuous wave EPR spectroscopy to establish that the KcsA W67F channel shows an altered pH dependence of activation. Structural studies on the W67F channel provide the structures of two intermediate states: a pre- open state and a pre-inactivated state of the KcsA channel. These structures highlight key nodes in the allosteric pathway. The structure of the KcsA W67F channel with the activation gate open shows altered ion occupancy at the second ion binding site (S2) in the selectivity filter. This finding in combination with previous studies strongly support a requirement for ion occupancy at the S2 site for the channel to inactivate.
Topics: Allosteric Regulation; Binding Sites; Ion Channel Gating; Models, Molecular; Mutation; Potassium Channels; Protein Binding; Protein Conformation; Structure-Activity Relationship
PubMed: 34627789
DOI: 10.1016/j.jmb.2021.167296 -
PloS One 2013N-type inactivation occurs when the N-terminus of a potassium channel binds into the open pore of the channel. This study examined the relationship between activation...
N-type inactivation occurs when the N-terminus of a potassium channel binds into the open pore of the channel. This study examined the relationship between activation and steady state inactivation for mutations affecting the N-type inactivation properties of the Aplysia potassium channel AKv1 expressed in Xenopus oocytes. The results show that the traditional single-step model for N-type inactivation fails to properly account for the observed relationship between steady state channel activation and inactivation curves. We find that the midpoint of the steady state inactivation curve depends in part on a secondary interaction between the channel core and a region of the N-terminus just proximal to the pore blocking peptide that we call the Inactivation Proximal (IP) region. The IP interaction with the channel core produces a negative shift in the activation and inactivation curves, without blocking the pore. A tripeptide motif in the IP region was identified in a large number of different N-type inactivation domains most likely reflecting convergent evolution in addition to direct descent. Point mutating a conserved hydrophobic residue in this motif eliminates the gating voltage shift, accelerates recovery from inactivation and decreases the amount of pore block produced during inactivation. The IP interaction we have identified likely stabilizes the open state and positions the pore blocking region of the N-terminus at the internal opening to the transmembrane pore by forming a Pre-Block (P state) interaction with residues lining the side window vestibule of the channel.
Topics: Algorithms; Amino Acid Motifs; Amino Acid Sequence; Animals; Conserved Sequence; Drosophila; Ion Channel Gating; Kinetics; Models, Biological; Models, Molecular; Molecular Sequence Data; Mutation; Oocytes; Potassium Channels; Protein Conformation; Protein Interaction Domains and Motifs; Sequence Alignment; Xenopus
PubMed: 24236164
DOI: 10.1371/journal.pone.0079891 -
Biochemistry Aug 2008KCNE1 is a single-span membrane protein that modulates the voltage-gated potassium channel KCNQ1 (K V7.1) by slowing activation and enhancing channel conductance to...
KCNE1 is a single-span membrane protein that modulates the voltage-gated potassium channel KCNQ1 (K V7.1) by slowing activation and enhancing channel conductance to generate the slow delayed rectifier current ( I Ks) that is critical for the repolarization phase of the cardiac action potential. Perturbation of channel function by inherited mutations in KCNE1 or KCNQ1 results in increased susceptibility to cardiac arrhythmias and sudden death with or without accompanying deafness. Here, we present the three-dimensional structure of KCNE1. The transmembrane domain (TMD) of KCNE1 is a curved alpha-helix and is flanked by intra- and extracellular domains comprised of alpha-helices joined by flexible linkers. Experimentally restrained docking of the KCNE1 TMD to a closed state model of KCNQ1 suggests that KCNE1 slows channel activation by sitting on and restricting the movement of the S4-S5 linker that connects the voltage sensor to the pore domain. We postulate that this is an adhesive interaction that must be disrupted before the channel can be opened in response to membrane depolarization. Docking to open KCNQ1 indicates that the extracellular end of the KCNE1 TMD forms an interface with an intersubunit cleft in the channel that is associated with most known gain-of-function disease mutations. Binding of KCNE1 to this "gain-of-function cleft" may explain how it increases conductance and stabilizes the open state. These working models for the KCNE1-KCNQ1 complexes may be used to formulate testable hypotheses for the molecular bases of disease phenotypes associated with the dozens of known inherited mutations in KCNE1 and KCNQ1.
Topics: Humans; KCNQ1 Potassium Channel; Magnetic Resonance Spectroscopy; Models, Biological; Potassium Channels, Voltage-Gated; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary
PubMed: 18611041
DOI: 10.1021/bi800875q -
The Biochemical Journal Jun 2017Mitochondria play an important role in tissue ischemia and reperfusion (IR) injury, with energetic failure and the opening of the mitochondrial permeability transition... (Review)
Review
Mitochondria play an important role in tissue ischemia and reperfusion (IR) injury, with energetic failure and the opening of the mitochondrial permeability transition pore being the major causes of IR-induced cell death. Thus, mitochondria are an appropriate focus for strategies to protect against IR injury. Two widely studied paradigms of IR protection, particularly in the field of cardiac IR, are ischemic preconditioning (IPC) and volatile anesthetic preconditioning (APC). While the molecular mechanisms recruited by these protective paradigms are not fully elucidated, a commonality is the involvement of mitochondrial K channel opening. In the case of IPC, research has focused on a mitochondrial ATP-sensitive K channel (mitoK), but, despite recent progress, the molecular identity of this channel remains a subject of contention. In the case of APC, early research suggested the existence of a mitochondrial large-conductance K (BK, big conductance of potassium) channel encoded by the gene, although more recent work has shown that the channel that underlies APC is in fact encoded by In this review, we discuss both the pharmacologic and genetic evidence for the existence and identity of mitochondrial K channels, and the role of these channels both in IR protection and in regulating normal mitochondrial function.
Topics: Allostasis; Animals; Cardiotonic Agents; Humans; Ion Channel Gating; Ischemic Preconditioning, Myocardial; KATP Channels; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Membrane Transport Modulators; Mitochondria, Heart; Models, Biological; Myocardial Ischemia; Myocardial Reperfusion Injury; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Sodium-Activated; Protein Isoforms; Terminology as Topic
PubMed: 28600454
DOI: 10.1042/BCJ20160623 -
The Journal of Biological Chemistry Oct 2001The slowly activating cardiac potassium current (I(Ks)) is generated by a heteromultimeric potassium channel complex consisting of pore-forming (KvLQT1) and accessory...
The slowly activating cardiac potassium current (I(Ks)) is generated by a heteromultimeric potassium channel complex consisting of pore-forming (KvLQT1) and accessory (minK) subunits belonging to the KCNQ and KCNE gene families, respectively. Evidence indicating that minK residues line the I(Ks) pore originates from the observation that two minK cysteine mutants (G55C and F54C) render I(Ks) Cd2+-sensitive. We have identified a single cysteine residue in the KvLQT1 S6 segment (Cys-331) that contributes to Cd2+ coordination in conjunction with cysteine residues engineered into the minK transmembrane domain. This observation indicates that minK resides in close proximity to S6 in the I(Ks) channel complex. On the basis of homology modeling that compares the KvLQT1 S6 segment with the structure of the bacterial potassium channel KcsA, we predict that the sulfhydryl side chain of Cys-331 projects away from the central axis of the KvLQT1 pore and suggest that minK resides outside of the permeation pathway. A preliminary model illustrating the orientation of minK with S6 was validated by successful prediction of a novel Cd2+ binding site created within the I(Ks) channel complex by engineering additional cysteine residues into both subunits. Our results indicate the location and orientation of minK within the I(Ks) channel complex and further suggest that Cd2+ exerts its effect on I(Ks) through an allosteric mechanism rather than direct pore blockade.
Topics: Animals; Binding Sites; Cadmium; Cysteine; Humans; KCNQ Potassium Channels; KCNQ1 Potassium Channel; Long QT Syndrome; Mutagenesis; Potassium Channels; Potassium Channels, Voltage-Gated; Protein Binding; Xenopus
PubMed: 11479291
DOI: 10.1074/jbc.M103956200