Abstract
Large-conductance voltage and Ca2+-activated potassium channels (BKCa) play a critical role in modulating contractile tone of smooth muscle, and neuronal processes. In most mammalian tissues, activation of beta-adrenergic receptors and protein kinase A (PKAc) increases BKCa channel activity, contributing to sympathetic nervous system/hormonal regulation of membrane excitability. Here we report the requirement of an association of the beta2-adrenergic receptor (beta2AR) with the pore forming alpha subunit of BKCa and an A-kinase-anchoring protein (AKAP79/150) for beta2 agonist regulation. beta2AR can simultaneously interact with both BKCa and L-type Ca2+ channels (Cav1.2) in vivo, which enables the assembly of a unique, highly localized signal transduction complex to mediate Ca2+- and phosphorylation-dependent modulation of BKCa current. Our findings reveal a novel function for G protein-coupled receptors as a scaffold to couple two families of ion channels into a physical and functional signaling complex to modulate beta-adrenergic regulation of membrane excitability.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Aorta / metabolism
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Brain / metabolism
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Calcium / metabolism*
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Cell Line
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Cloning, Molecular
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Dimerization
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Electrophysiology
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Female
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Gene Expression Regulation
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Glutathione Transferase / metabolism
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Humans
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Immunohistochemistry
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Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
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Lung / metabolism
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Models, Biological
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Muscle, Smooth / metabolism
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Oocytes / physiology
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Patch-Clamp Techniques
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Phosphorylation
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Potassium Channels / genetics
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Potassium Channels / metabolism*
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Potassium Channels, Calcium-Activated / metabolism*
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Precipitin Tests
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RNA, Messenger / genetics
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Rats
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Receptors, Adrenergic, beta-2 / chemistry
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Receptors, Adrenergic, beta-2 / genetics
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Receptors, Adrenergic, beta-2 / metabolism*
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Signal Transduction
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Up-Regulation
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Urinary Bladder / metabolism
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Xenopus
Substances
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Kcnma1 protein, rat
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Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
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Potassium Channels
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Potassium Channels, Calcium-Activated
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RNA, Messenger
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Receptors, Adrenergic, beta-2
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Recombinant Fusion Proteins
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Glutathione Transferase
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Calcium