AKAPs as antiarrhythmic targets?
Phosphorylation of ion channels plays a critical role in the modulation and amplification of biophysical signals. Kinases and phosphatases have broad substrate recognition sequences. Therefore, the targeting of kinases and phosphatases to specific sites enhances the regulation of diverse signaling events. Ion channel macromolecular complexes can be formed by the association of A-kinase anchoring proteins (AKAPs) or other adaptor proteins directly with the channel. The discovery that leucine/isoleucine zippers play an important role in the recruitment of phosphorylation-modulatory proteins to certain ion channels has permitted the elucidation of specific ion channel macromolecular complexes. Disruption of signaling complexes by genetic defects can lead to abnormal physiological function. This chapter will focus on evidence supporting the concept that ion channel macromolecular complex formation plays an important role in regulating channel function in normal and diseased states. Moreover, we demonstrate that abnormal complex formation may directly lead to abnormal channel regulation by cellular signaling pathways, potentially leading to arrhythmogenesis and cardiac dysfunction.
Marx
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Division of Cardiology, Department of Medicine and Pharmacology, Columbia University College of Physicians and Surgeons, 630 W 168th St., New York, NY 10032, USA. sm460@columbia.edu
Kurokawa
J
J
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000502:physiology*; D020816:Amino Acid Motifs; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000502:physiology; D051668:Delayed Rectifier Potassium Channels / Q000502:physiology; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000502:physiology
D054758:A Kinase Anchor Proteins; C119719:AKAP9 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000889:Anti-Arrhythmia Agents; D003598:Cytoskeletal Proteins; D051668:Delayed Rectifier Potassium Channels; C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases