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The Journal of Neuroscience, April 5, 2006, 26(14):3757-3766; doi:10.1523/JNEUROSCI.5017-05.2006
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Cellular/Molecular
Structural Determinants of M-Type KCNQ (Kv7) K+ Channel Assembly
Michael Schwake,1 Despina Athanasiadu,2 Christian Beimgraben,1 Judith Blanz,3 Christian Beck,4 Thomas J. Jentsch,3 Paul Saftig,1 andThomas Friedrich2 1Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, D-24098 Kiel, Germany, 2Max-Planck-Institut für Biophysik, D-60438 Frankfurt, Germany, 3Zentrum für Molekulare Neurobiologie Hamburg, D-20251 Hamburg, Germany, and 4Universitätsklinikum Schleswig-Holstein, Campus Kiel, II Medizinische Klinik, Sektion Stammzell- und Immuntherapie, 24105 Kiel
Correspondence should be addressed to either of the following: Michael Schwake, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany, Email: mschwake{at}biochem.uni-kiel.de; or Thomas Friedrich, Center for Innovative Competence MacroNano, Technical University of Ilmenau, Center for Micro- and Nanotechnologies, Gustav-Kirchhoff-Strasse 7, D-98693 Ilmenau, Germany, Thomas.Friedrich{at}mpibp-frankfurt.mpg.de
The ability of KCNQ (Kv7) channels to form hetero-oligomers is of high physiological importance, because heteromers of KCNQ3 with KCNQ2 or KCNQ5 underlie the neuronal M-current, which modulates neuronal excitability. In KCNQ channels, we recently identified a C-terminal subunit interaction (si) domain that determines their subunit-specific assembly. Within this si domain, there are two motifs that comprise
30 amino acid residues each and that exhibit a high probability for coiled-coil formation. Transfer of the first or the second coiled-coil (TCC) domain from KCNQ3 into the KCNQ1 scaffold resulted in chimeras KCNQ1(TCC1)Q3 and KCNQ1(TCC2)Q3, both of which coimmunoprecipitated with KCNQ2. However, only KCNQ1(TCC2)Q3 enhanced KCNQ2 currents and surface expression or exerted a strong dominant-negative effect on KCNQ2. Deletion of TCC2 within KCNQ2 yielded functional homomeric channels but prevented the current augmentation measured after coexpression of KCNQ2 and KCNQ3. In contrast, deleting TCC1 within KCNQ2 did not give functional homomeric KCNQ2 or heteromeric KCNQ2/KCNQ3 channels. Mutations that disrupted the predicted coiled-coil structure of TCC1 in KCNQ2 or KCNQ3 abolished channel activity after expressing these constructs singly or in combination, whereas helix-breaking mutations in TCC2 of KCNQ2 gave functional homomeric channels but prevented the heteromerization with KCNQ3. In contrast, KCNQ3 carrying a coiled-coil disrupting mutation in TCC2 hetero-oligomerized with KCNQ2.
Our data suggest that the TCC1 domains of KCNQ2 and KCNQ3 are required to form functional homomeric as well as heteromeric channels, whereas both TCC2 domains facilitate an efficient transport of heteromeric KCNQ2/KCNQ3 channels to the plasma membrane.
Key words: epilepsy; KCNQ; M-current; potassium channels; coiled-coil; tetramerization
Received July 28, 2005; revised Feb. 13, 2006; accepted Feb. 13, 2006.
Correspondence should be addressed to either of the following: Michael Schwake, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany, Email: mschwake{at}biochem.uni-kiel.de; or Thomas Friedrich, Center for Innovative Competence MacroNano, Technical University of Ilmenau, Center for Micro- and Nanotechnologies, Gustav-Kirchhoff-Strasse 7, D-98693 Ilmenau, Germany, Thomas.Friedrich{at}mpibp-frankfurt.mpg.de
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