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The Journal of Neuroscience, February 28, 2007, 27(9):2369-2376; doi:10.1523/JNEUROSCI.3565-06.2007

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Cellular/Molecular
Organization and Regulation of Small Conductance Ca²⁺-activated K⁺ Channel Multiprotein Complexes

Duane Allen,³ Bernd Fakler,¹ James Maylie,² and John P. Adelman³

¹Department of Physiology, University of Freiburg, Freiburg 09599, Germany, and ²Department of Obstetrics and Gynecology, and ³Vollum Institute, Oregon Health and Science University, Portland, Oregon 97329

Correspondence should be addressed to Dr. John P. Adelman, Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97329. Email: adelman{at}ohsu.edu

Small conductance Ca²⁺-activated K⁺ channels (SK channels) are complexes of four pore-forming subunits each bound by calmodulin (CaM) that mediate Ca²⁺ gating. Proteomic analysis indicated that SK2 channels also bind protein kinase CK2 (CK2) and protein phosphatase 2A (PP2A). Coexpression of SK2 with the CaM phosphorylation surrogate CaM(T80D) suggested that the apparent Ca²⁺ sensitivity of SK2 channels is reduced by CK2 phosphorylation of SK2-bound CaM. By using 4,5,6,7-tetrabromo-2-azabenzimidazole, a CK2-specific inhibitor, we confirmed that SK2 channels coassemble with CK2. PP2A also binds to SK2 channels and counterbalances the effects of CK2, as shown by coexpression of a dominant-negative mutant PP2A as well as a mutant SK2 channel no longer able to bind PP2A. In vitro binding studies have revealed interactions between the N and C termini of the channel subunits as well as interactions among CK2 and ß subunits, PP2A, and distinct domains of the channel. In the channel complex, lysine residue 121 within the N-terminal domain of the channel activates SK2-bound CK2, and phosphorylation of CaM is state dependent, occurring only when the channels are closed. The effects of CK2 and PP2A indicate that native SK2 channels are multiprotein complexes that contain constitutively associated CaM, both subunits of CK2, and at least two different subunits of PP2A. The results also show that the Ca²⁺ sensitivity of SK2 channels is regulated in a dynamic manner, directly through CK2 and PP2A, and indirectly by Ca²⁺ itself via the state dependence of CaM phosphorylation by CK2.

Key words: SK channels; microdomain; kinase; phosphatase; state dependence; regulation

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Received Aug. 17, 2006; revised Jan. 25, 2007; accepted Jan. 26, 2007.

Correspondence should be addressed to Dr. John P. Adelman, Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97329. Email: adelman{at}ohsu.edu

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