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Vol. 52, Issue 4, 557-594, December 2000

Potassium Channels: Molecular Defects, Diseases, and Therapeutic Opportunities

Char-Chang Shieh1, Michael Coghlan, James P. Sullivan and Murali Gopalakrishnan

Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois

I. Background
    A. Channel Diversity and Classification
        1. Six Transmembrane One-Pore Channels.
            a. Pore and Selectivity Filter.
            b. Voltage Sensor and Channel Activation.
            c. Inactivation.
            d. Subunit Interaction and Assembly Domains.
        2. Two Transmembrane One-Pore Channels.
        3. Four Transmembrane Two-Pore Channels.
    B. Auxiliary Subunits
    C. Crystal Structure of K+ Channels
II. Pathophysiologic Regulation of K+ Channels: Genetically Linked Diseases
    A. Cardiac Diseases
        1. Long-QT1 and Long-QT5 Syndromes: KCNQ1 (KvLQT1) and minK.
        2. Long-QT2 Syndrome and Human ether-a-go-go-Related K+ Channel.
    B. Neuronal Diseases
        1. Episodic Ataxia/Myokymia and Kv1.1.
        2. Benign Familial Neonatal Convulsions and KCNQ2/KCNQ3.
        3. Neurodegeneration and Kir3.2.
        4. Schizophrenia and SK3 (hKCa3).
    C. Hearing and Vestibular Diseases: Nonsyndromic Dominant Deafness and KCNQ4
    D. Renal Diseases: Bartter's Syndrome and Kir1.1
    E. Metabolic Diseases: Familial Persistent Hyperinsulinemic Hypoglycemia of Infancy and Sulfonylurea Receptor 1
III. Disease- and Drug-Induced Regulation of K+ Channels
    A. Cardiac Failure and Hypertrophy
    B. Atrial Fibrillation
    C. Drug-Induced Long-QT Syndromes
    D. Apoptosis and Oncogenesis
        1. Apoptosis.
        2. Oncogenesis.
    E. Alzheimer's Disease
        1. beta -Amyloid.
        2. beta -Amyloid Protein Precursor.
        3. Presenilins.
    F. Neuromuscular Disorders
IV. Pharmacological Considerations
    A. Voltage-Gated K+ Channels
        1. Kv1.3 Channels.
        2. Cardiac Delayed Rectifier K+ Channels.
        3. KCNQ2/KCNQ3 Channels.
    B. Calcium-Activated K+ Channels
        1. Large Conductance Channels.
        2. Intermediate Conductance Channels.
        3. Small Conductance Channels.
    C. ATP-Sensitive K+ Channels
    D. Two-Pore K+ Channels
V. Concluding Remarks
References

Potassium channels play important roles in vital cellular signaling processes in both excitable and nonexcitable cells. Over 50 human genes encoding various K+ channels have been cloned during the past decade, and precise biophysical properties, subunit stoichiometry, channel assembly, and modulation by second messenger and ligands have been elucidated to a large extent. Recent advances in genetic linkage analysis have greatly facilitated the identification of many disease-producing loci, and naturally occurring mutations in various K+ channels have been identified in diseases such as long-QT syndromes, episodic ataxia/myokymia, familial convulsions, hearing and vestibular diseases, Bartter's syndrome, and familial persistent hyperinsulinemic hypoglycemia of infancy. In addition, changes in K+ channel function have been associated with cardiac hypertrophy and failure, apoptosis and oncogenesis, and various neurodegenerative and neuromuscular disorders. This review aims to 1) provide an understanding of K+ channel function at the molecular level in the context of disease processes and 2) discuss the progress, hurdles, challenges, and opportunities in the exploitation of K+ channels as therapeutic targets by pharmacological and emerging genetic approaches.

1 Address for correspondence: Char-Chang Shieh, Ph.D., Dept. 47C, Bldg. AP9A 3rd Floor, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064. E-mail: char-chang.shieh{at}abbott.com

0031-6997/00/5204-0557$03.00/0
PHARMACOLOGICAL REVIEWS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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