Ca(2+)/calmodulin regulates Kvβ1.1-mediated inactivation of voltage-gated K(+) channels.
A-type K(+) channels open on membrane depolarization and undergo subsequent rapid inactivation such that they are ideally suited for fine-tuning the electrical signaling in neurons and muscle cells. Channel inactivation mostly follows the so-called ball-and-chain mechanism, in which the N-terminal structures of either the K(+) channel's α or β subunits occlude the channel pore entry facing the cytosol. Inactivation of Kv1.1 and Kv1.4 channels induced by Kvβ1.1 subunits is profoundly decelerated in response to a rise in the intracellular Ca(2+) concentration, thus making the affected channel complexes negative feedback regulators to limit neuronal overexcitation. With electrophysiological and biochemical experiments we show that the Ca(2+) dependence is gained by binding of calmodulin to the "chain" segment of Kvβ1.1 thereby compromising the mobility of the inactivation particle. Furthermore, inactivation regulation via Ca(2+)/calmodulin does not interfere with the β subunit's enzymatic activity as an NADPH-dependent oxidoreductase, thus rendering the Kvβ1.1 subunit a multifunctional receptor that integrates cytosolic signals to be transduced to altered electrical cellular activity.
Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena &Jena University Hospital, Hans-Knöll-Str. 2, D-07745 Jena, Germany.
Sandip M
SM
Swain
Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena &Jena University Hospital, Hans-Knöll-Str. 2, D-07745 Jena, Germany.
Nirakar
N
Sahoo
Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena &Jena University Hospital, Hans-Knöll-Str. 2, D-07745 Jena, Germany.
Sophie
S
Dennhardt
Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena &Jena University Hospital, Hans-Knöll-Str. 2, D-07745 Jena, Germany.
Roland
R
Schönherr
Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena &Jena University Hospital, Hans-Knöll-Str. 2, D-07745 Jena, Germany.
Stefan H
SH
Heinemann
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D051662:Kv1.1 Potassium Channel / Q000378:metabolism*; D051663:Kv1.2 Potassium Channel / Q000378:metabolism; D032342:Muscle Cells / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D016062:Porosity; D051381:Rats; D014981:Xenopus
D002147:Calmodulin; D051663:Kv1.2 Potassium Channel; D051662:Kv1.1 Potassium Channel; D009247:NADH, NADPH Oxidoreductases; D002118:Calcium