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The Journal of Neuroscience, October 15, 1999, 19(20):8830-8838

Domains Responsible for Constitutive and Ca²⁺-Dependent Interactions between Calmodulin and Small Conductance Ca²⁺-Activated Potassium Channels

John E. Keen¹, Radwan Khawaled¹, David L. Farrens², Torben Neelands¹, Andre Rivard¹, Chris T. Bond¹, Aaron Janowsky⁴, Bernd Fakler⁵, John P. Adelman¹, and James Maylie³

¹ Vollum Institute, ² Departments of Biochemistry and Molecular Biology, ³ Obstetrics and Gynecology, and ⁴ Research Service, Veteran's Administration Medical Center, and Department of Psychiatry, Behavioral Neuroscience, and Physiology and Pharmacology, Oregon Health Sciences University, Portland Oregon, 97201, and ⁵ Department of Physiology, University of Tüebingen, Tüebingen, Germany

Small conductance Ca²⁺-activated potassium channels (SK channels) are coassembled complexes of pore-forming SK  subunits and calmodulin. We proposed a model for channel activation in which Ca²⁺ binding to calmodulin induces conformational rearrangements in calmodulin and the  subunits that result in channel gating. We now report fluorescence measurements that indicate conformational changes in the  subunit after calmodulin binding and Ca²⁺ binding to the  subunit-calmodulin complex. Two-hybrid experiments showed that the Ca²⁺-independent interaction of calmodulin with the  subunits requires only the C-terminal domain of calmodulin and is mediated by two noncontiguous subregions; the ability of the E-F hands to bind Ca²⁺ is not required. Although SK  subunits lack a consensus calmodulin-binding motif, mutagenesis experiments identified two positively charged residues required for Ca²⁺-independent interactions with calmodulin. Electrophysiological recordings of SK2 channels in membrane patches from oocytes coexpressing mutant calmodulins revealed that channel gating is mediated by Ca²⁺ binding to the first and second E-F hand motifs in the N-terminal domain of calmodulin. Taken together, the results support a calmodulin- and Ca²⁺-calmodulin-dependent conformational change in the channel  subunits, in which different domains of calmodulin are responsible for Ca²⁺-dependent and Ca²⁺-independent interactions. In addition, calmodulin is associated with each  subunit and must bind at least one Ca²⁺ ion for channel gating. Based on these results, a state model for Ca²⁺ gating was developed that simulates alterations in SK channel Ca²⁺ sensitivity and cooperativity associated with mutations in CaM.

Key words: SK channels; afterhyperpolarization; calmodulin; Ca²⁺-gating; Ca²⁺-independent interactions; state model

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19208830-09$05.00/0

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