Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel.
Beta-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 (I(Ks)). Mutations in either KCNQ1 or KCNE1, the I(Ks) subunits, 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.
Kurokawa
Junko
J
Department of Pharmacology, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, New York, NY 10032, USA.
Chen
Lei
L
Kass
Robert S
RS
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D006321:Heart / Q000502:physiology*; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D010766:Phosphorylation; D015221:Potassium Channels / Q000737:chemistry / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated
D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk); D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases