The Ca2+-Activated K+ Channel of Intermediate Conductance: A Molecular Target for Novel Treatments?
Abstract:This review discusses the Ca2+-activated K+ channels of intermediate conductance (IK channels), and their historical discovery in erythrocytes, their classical biophysical characteristics, physiological function, molecular biology as well as their role as possible molecular targets for pharmacological intervention in various diseases. The first described Ca2+-activated K+ channel ever - the so-called Gardos channel from human erythrocytes - is an IK channel. The “I” denominates the intermediate conductance that distinguishes the IK channels from the related Ca2+- activated K+ channels of small (SK) or large (BK) conductance. The recent cloning of the human IK channel gene (KCNN4) enabled a detailed mapping of the expression in various tissues. IK channel expression is found predominately in cells of the blood, in epithelia and endothelia. An important physiological role of IK channels is to set the membrane potential at fairly negative values and thereby to build up large electrical gradients for the passive transport of ions such as Cl- efflux driving water and Na+ secretion from epithelia, and Ca2+ influx controlling Tlymphocyte proliferation.
The molecular cloning of IK and SK channels has revealed that both channels gain their Ca2+-sensitivity from tightly bound calmodulin (CaM). The IK channel is potently blocked by the scorpion toxin charybdotoxin (ChTx) and the antimycotic clotrimazole (CLT). CLT has been in clinical trials for the treatment of sickle cell disease, diarrhea and ameliorates the symptoms of rheumatoid arthritis. However, inhibition of cytochrome P450 enzymes by CLT limits its therapeutic value, but new drug candidates are entering the stage.
It is discussed whether pharmacological modulation of IK channels may be beneficial in sickle cell anemia, cystic fibrosis, secretory diarrhea, craft-versus-host disease and autoimmune diseases.
Document Type: Review Article
Publication date: December 1, 2001
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- Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.