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Nature Jun 2001Many voltage-dependent K+ channels open when the membrane is depolarized and then rapidly close by a process called inactivation. Neurons use inactivating K+ channels to...
Many voltage-dependent K+ channels open when the membrane is depolarized and then rapidly close by a process called inactivation. Neurons use inactivating K+ channels to modulate their firing frequency. In Shaker-type K+ channels, the inactivation gate, which is responsible for the closing of the channel, is formed by the channel's cytoplasmic amino terminus. Here we show that the central cavity and inner pore of the K+ channel form the receptor site for both the inactivation gate and small-molecule inhibitors. We propose that inactivation occurs by a sequential reaction in which the gate binds initially to the cytoplasmic channel surface and then enters the pore as an extended peptide. This mechanism accounts for the functional properties of K+ channel inactivation and indicates that the cavity may be the site of action for certain drugs that alter cation channel function.
Topics: Amines; Amino Acid Sequence; Animals; Bacterial Proteins; Crystallography, X-Ray; Ion Channel Gating; Models, Molecular; Molecular Sequence Data; Mutagenesis; Potassium Channel Blockers; Potassium Channels; Protein Conformation; Quaternary Ammonium Compounds; Recombinant Proteins; Sequence Alignment; Shaker Superfamily of Potassium Channels; Xenopus
PubMed: 11395760
DOI: 10.1038/35079500 -
Expert Opinion on Investigational Drugs Jul 2001Potassium channel openers (KCOs) are important tools that are often used to gain a greater understanding of K(+) channels. Agents that can induce or maintain the opening... (Review)
Review
Potassium channel openers (KCOs) are important tools that are often used to gain a greater understanding of K(+) channels. Agents that can induce or maintain the opening of K(+) channels also offer a therapeutic approach to controlling of cell excitability and offer a means of producing stability in biological systems. The pathogenesis of a broad range of peripheral disorders (e.g., LQT syndrome, hypokalemic periodic paralysis, hyperinsulinism in infancy and erectile dysfunction) are associated with dysfunctional K(+) channels due to mutations in genes encoding channel proteins. The therapeutic potential of KCOs in peripheral K(+) channelopathies is discussed. The identification of K(+) channel subtype-specific openers offers discrete modulation of cellular systems creating a realistic therapeutic advance in the treatment of K(+) channelopathies.
Topics: Adenosine Triphosphatases; Drugs, Investigational; Ion Channel Gating; Potassium Channels
PubMed: 11772256
DOI: 10.1517/13543784.10.7.1345 -
Science (New York, N.Y.) May 1991Voltage-gated potassium channels make up a large molecular family of integral membrane proteins that are fundamentally involved in the generation of bioelectric signals... (Review)
Review
Voltage-gated potassium channels make up a large molecular family of integral membrane proteins that are fundamentally involved in the generation of bioelectric signals such as nerve impulses. These proteins span the cell membrane, forming potassium-selective pores that are rapidly switched open or closed by changes in membrane voltage. After the cloning of the first potassium channel over 3 years ago, recombinant DNA manipulation of potassium channel genes is now leading to a molecular understanding of potassium channel behavior. During the past year, functional domains responsible for channel gating and potassium selectivity have been identified, and detailed structural pictures underlying these functions are beginning to emerge.
Topics: Action Potentials; Amino Acid Sequence; Animals; Ion Channel Gating; Models, Structural; Molecular Sequence Data; Potassium Channels; Protein Conformation
PubMed: 2031183
DOI: 10.1126/science.252.5009.1092 -
Science (New York, N.Y.) Jan 1998Benign familial neonatal convulsions (BFNC) is an autosomal dominant epilepsy of infancy, with loci mapped to human chromosomes 20q13.3 and 8q24. By positional cloning,...
Benign familial neonatal convulsions (BFNC) is an autosomal dominant epilepsy of infancy, with loci mapped to human chromosomes 20q13.3 and 8q24. By positional cloning, a potassium channel gene (KCNQ2) located on 20q13.3 was isolated and found to be expressed in brain. Expression of KCNQ2 in frog (Xenopus laevis) oocytes led to potassium-selective currents that activated slowly with depolarization. In a large pedigree with BFNC, a five-base pair insertion would delete more than 300 amino acids from the KCNQ2 carboxyl terminus. Expression of the mutant channel did not yield measurable currents. Thus, impairment of potassium-dependent repolarization is likely to cause this age-specific epileptic syndrome.
Topics: Action Potentials; Amino Acid Sequence; Animals; Brain; Chromosome Mapping; Chromosomes, Human, Pair 20; Cloning, Molecular; Epilepsy; Female; Frameshift Mutation; Humans; Infant, Newborn; KCNQ2 Potassium Channel; Male; Molecular Sequence Data; Mutagenesis, Insertional; Oocytes; Open Reading Frames; Pedigree; Potassium; Potassium Channels; Potassium Channels, Voltage-Gated; Xenopus laevis
PubMed: 9430594
DOI: 10.1126/science.279.5349.403 -
Trends in Cardiovascular Medicine Jul 2000Protein kinase A is an enzyme that regulates many cellular processes and is activated in many pathological conditions such as stress and various types of heart failure.... (Review)
Review
Protein kinase A is an enzyme that regulates many cellular processes and is activated in many pathological conditions such as stress and various types of heart failure. Recently it has been shown that protein kinase A couples functionally to the HERG cardiac potassium channel, thereby altering repolarization in the heart. This link between a repolarizing potassium channel and the protein kinase system of cardiac cells may contribute to arrhythmogenesis and may become a target for future approaches to antiarrhythmic therapy.
Topics: Animals; Cation Transport Proteins; Cyclic AMP-Dependent Protein Kinases; DNA-Binding Proteins; ERG1 Potassium Channel; Electrophysiology; Ether-A-Go-Go Potassium Channels; Heart; Humans; Potassium Channels; Potassium Channels, Voltage-Gated; Trans-Activators; Transcriptional Regulator ERG
PubMed: 11282296
DOI: 10.1016/s1050-1738(00)00071-2 -
Acta Myologica : Myopathies and... May 2004
Topics: Humans; Kv1.1 Potassium Channel; Mutation, Missense; Myokymia; Potassium Channels; Potassium Channels, Voltage-Gated
PubMed: 15298080
DOI: No ID Found -
Peptides Oct 2018Recent reports have identified defensins as a new type of potassium channel inhibitors; differential binding mechanisms of human β-defensins hBD1 and hBD2 point to...
Recent reports have identified defensins as a new type of potassium channel inhibitors; differential binding mechanisms of human β-defensins hBD1 and hBD2 point to complex interactions between human β-defensins and potassium channels. We investigated the inhibitory effects of human defensins hBD3 and hBD4 on potassium channels. The data indicate that hBD3 is a voltage-gated channel subfamily A member 3 (Kv1.3) inhibitor with an IC value of 187.6 ± 25.7 nM; 1 μM hBD4 inhibited 34.0 ± 0.2% of Kv1.3 channel currents. Moreover, 1 μM hBD3 inhibited 50.6 ± 3.6% of Kv1.2 channel currents and had smaller effects on Kv1.1, SKCa3, and IKCa channel currents; these effects differed from the Kv1.3 channel-specific inhibitors hBD1 and hBD2. Similar to the pharmacological profiles of hBD1 and hBD2, hBD4 had lower inhibitory effects on Kv1.1, Kv1.2, SKCa3, and IKCa channels. Subsequent mutagenesis and channel activation experiments confirmed that hBD3 binds in a manner similar to that of hBD1, interacting with the outer pore region of the Kv1.3 channel without affecting Kv1.3 channel activation. Thus, the data indicate that the human β-defensin family is a novel group of potassium channel inhibitors with diverse types of human β-defensin-potassium channel interactions.
Topics: HEK293 Cells; Humans; Intermediate-Conductance Calcium-Activated Potassium Channels; Kinetics; Kv1.2 Potassium Channel; Kv1.3 Potassium Channel; Potassium Channel Blockers; Potassium Channels; Small-Conductance Calcium-Activated Potassium Channels; beta-Defensins
PubMed: 30121363
DOI: 10.1016/j.peptides.2018.08.005 -
Quarterly Reviews of Biophysics Nov 1998
Review
Topics: Animals; Humans; Multigene Family; Mutation; Potassium Channels; Potassium Channels, Voltage-Gated
PubMed: 10709243
DOI: 10.1017/s0033583599003467 -
American Journal of Physiology.... Mar 2002
Review
Topics: Animals; Humans; Hypokalemia; Long QT Syndrome; Mutation, Missense; Potassium Channels; Potassium Channels, Voltage-Gated
PubMed: 11832381
DOI: 10.1152/ajpregu.00723.2001 -
Journal of Biological Regulators and... 2010The involvement of a number of potassium channels has been reported in respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD), supporting...
The involvement of a number of potassium channels has been reported in respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD), supporting the idea that potassium channel modulating agents may help control it. Experimental evidence and preclinical models suggest that ATP-dependent K(+) (K(ATP)) channel openers, big-conductance K(+) (BK(CA)) channel openers, and intermediate-conductance K(+) (IK(CA)) channel blockers may be the most effective agents for treating asthma and COPD. Modulation of potassium channels by these agents may produce beneficial effects such as bronchodilation, a reduction in airways hyperresponsiveness (AHR), a reduction in cough and mucus production and an inhibition in airway inflammation and remodelling. The aim of this paper is to investigate the role of K(+) channel modulation in the pathogenesis, progression and exacerbation of asthma and COPD, and to review the evidence suggesting that K(+) channel modulators may be a valuable treatment option for these respiratory diseases.
Topics: Asthma; Bronchodilator Agents; Humans; Intermediate-Conductance Calcium-Activated Potassium Channels; KATP Channels; Large-Conductance Calcium-Activated Potassium Channels; Potassium Channel Blockers; Potassium Channels; Pulmonary Disease, Chronic Obstructive
PubMed: 20487625
DOI: No ID Found