Reversible tyrosine protein phosphorylation regulates large conductance voltage- and calcium-activated potassium channels via cortactin.
Large conductance calcium- and voltage-activated potassium (BK) channels assemble as macromolecular signaling complexes and are potently regulated by reversible protein phosphorylation. However, although numerous studies have revealed regulation of BK channels through changes in direct phosphorylation of the pore-forming alpha-subunits the functional role of changes in phosphorylation of defined adapter/signaling proteins within the complex on channel function are essentially not known. Here, we demonstrate that mammalian BK channels are potently regulated by endogenous protein-tyrosine kinase and protein-tyrosine phosphatase activity closely associated with the channel. BK channel regulation was not dependent upon direct phosphorylation of the BK alpha-subunit, rather channel function was controlled by the tyrosine phosphorylation status of the adapter protein cortactin that assembles directly with the BK channel. Our data thus reveal a novel mode for BK channel regulation by reversible tyrosine phosphorylation and strongly support the hypothesis that phosphorylation-dependent regulation of accessory proteins within the BK channel signaling complex represents an important target for control of BK channel function.
Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, Scotland, United Kingdom.
Lijun
L
Tian
Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, Scotland, United Kingdom.
Heather
H
McClafferty
Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, Scotland, United Kingdom.
Lie
L
Chen
Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, Scotland, United Kingdom. Electronic address: mike.shipston@ed.ac.uk.
Michael J
MJ
Shipston
D000199:Actins / Q000378:metabolism; D002460:Cell Line; D051356:Cortactin / Q000737:chemistry / Q000502:physiology*; D015638:Cytochalasin D / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004594:Electrophysiology / Q000379:methods; D005786:Gene Expression Regulation; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D018408:Patch-Clamp Techniques / Q000379:methods; D010590:Phalloidine / Q000378:metabolism; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry*
D000199:Actins; C495868:CTTN protein, human; D051356:Cortactin; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010590:Phalloidine; D015638:Cytochalasin D; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases