Functional expression of two KvLQT1-related potassium channels responsible for an inherited idiopathic epilepsy.
Benign familial neonatal convulsions (BFNC), a class of idiopathic generalized epilepsy, is an autosomal dominantly inherited disorder of newborns. BFNC has been linked to mutations in two putative K+ channel genes, KCNQ2 and KCNQ3. Amino acid sequence comparison reveals that both genes share strong homology to KvLQT1, the potassium channel encoded by KCNQ1, which is responsible for over 50% of inherited long QT syndrome. Here we describe the cloning, functional expression, and characterization of K+ channels encoded by KCNQ2 and KCNQ3 cDNAs. Individually, expression of KCNQ2 or KCNQ3 in Xenopus oocytes elicits voltage-gated, rapidly activating K+-selective currents similar to KCNQ1. However, unlike KCNQ1, KCNQ2 and KCNQ3 currents are not augmented by coexpression with the KCNQ1 beta subunit, KCNE1 (minK, IsK). Northern blot analyses reveal that KCNQ2 and KCNQ3 exhibit similar expression patterns in different regions within the brain. Interestingly, coexpression of KCNQ2 and KCNQ3 results in a substantial synergistic increase in current amplitude. Coexpression of KCNE1 with the two channels strongly suppressed current amplitude and slowed kinetics of activation. The pharmacological and biophysical properties of the K+ currents observed in the coinjected oocytes differ somewhat from those observed after injecting either KCNQ2 or KCNQ3 by itself. The functional interaction between KCNQ2 and KCNQ3 provides a framework for understanding how mutations in either channel can cause a form of idiopathic generalized epilepsy.
Yang
W P
WP
Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Levesque
P C
PC
Little
W A
WA
Conder
M L
ML
Ramakrishnan
P
P
Neubauer
M G
MG
Blanar
M A
MA
D000818:Animals; D001921:Brain / Q000378:metabolism; D003001:Cloning, Molecular; D004594:Electrophysiology; D004829:Epilepsy, Generalized / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D008845:Microinjections; D009865:Oocytes / Q000502:physiology; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger / Q000378:metabolism; D014981:Xenopus
D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D051659:KCNQ3 Potassium Channel; C496916:KCNQ3 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; C059983:potassium channel protein I(sk)