Requirement of Subunit Expression for cAMP-Mediated Regulation of a Heart Potassium Channel

β-Adrenergic receptor stimulation increases heart rate and shortens ventricular action-potential duration, the latter effect due in part to a cAMP-dependent increase in the slow outward potassium current (IKs). Mutations in either KCNQ1 or KCNE1, the IKssubunits, are associated with variants (LQT-1...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2003-02, Vol.100 (4), p.2122-2127
Main Authors: Kurokawa, Junko, Chen, Lei, Kass, Robert S.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Antibodies
Biological Sciences
CHO Cells
Cricetinae
Cyclic AMP - physiology
Cyclic AMP-Dependent Protein Kinases - physiology
Dialysis
Electric potential
Face
Gene expression regulation
Genetic mutation
Heart
Heart - physiology
KCNQ Potassium Channels
KCNQ1 Potassium Channel
Neurotransmitters
Phosphorylation
Physiological regulation
Potassium
Potassium Channels - chemistry
Potassium Channels - physiology
Potassium Channels, Voltage-Gated
Proteins
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Summary:β-Adrenergic receptor stimulation increases heart rate and shortens ventricular action-potential duration, the latter effect due in part to a cAMP-dependent increase in the slow outward potassium current (IKs). Mutations in either KCNQ1 or KCNE1, the IKssubunits, are associated with variants (LQT-1 and LQT-5) of the congenital long QT syndrome. We now show that cAMP-mediated functional regulation of KCNQ1/KCNE1 channels, a consequence of cAMP-dependent protein kinase A phosphorylation of the KCNQ1 N terminus, requires coexpression of KCNQ1 with KCNE1, its auxiliary subunit. Further, at least two KCNE1 mutations linked to LQT-5 (D76N and W87R) cause functional disruption of cAMP-mediated KCNQ1/KCNE1-channel regulation despite the response of the substrate protein (KCNQ1) to protein kinase A phosphorylation. Transduction of protein phosphorylation into physiologically necessary channel function represents a previously uncharacterized role for the KCNE1 auxiliary subunit, which can be disrupted in LQT-5.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0434935100