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J. Biol. Chem. 277 (46): 43724-43729

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Reciprocal Modulation between the alpha  and beta 4 Subunits of hSlo Calcium-dependent Potassium Channels*

Ping JinDagger §, Thomas M. WeigerDagger ||§, and Irwin B. LevitanDagger

From the Dagger  Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 and || Department of Molecular Neuroscience and Cell Physiology, University of Salzburg, Institute of Zoology, Hellbrunnerstrasse 34, A-5020 Salzburg, Austria

Large conductance Ca2+-dependent potassium (KCa or maxi K) channels are composed of a pore-forming alpha  subunit and an auxiliary beta  subunit. We have shown that the brain-specific beta 4 subunit modulates the voltage dependence, activation kinetics, and toxin sensitivity of the hSlo channel (Weiger, T. M., Holmqvist, M. H., Levitan, I. B., Clark, F. T., Sprague, S., Huang, W. J., Ge, P., Wang, C., Lawson, D., Jurman, M. E., Glucksmann, M. A., Silos-Santiago, I., DiStefano, P. S., and Curtis, R. (2000) J. Neurosci. 20, 3563-3570). We investigated here the N-linked glycosylation of the beta 4 subunit and its effect on the modulation of the hSlo alpha  subunit. When expressed alone in HEK293 cells, the beta 4 subunit runs as a single molecular weight band on an SDS gel. However, when coexpressed with the hSlo alpha  subunit, the beta 4 subunit appears as two different molecular weight bands. Enzymatic deglycosylation or mutation of the N-linked glycosylation residues in beta 4 converts it to a single lower molecular weight band, even in the presence of the hSlo alpha  subunit, suggesting that the beta 4 subunit can be present as an immature, core glycosylated form and a mature, highly glycosylated form. Blockage of protein transport from the endoplasmic reticulum to the Golgi compartment with brefeldin A abolishes the mature, highly glycosylated beta 4 band. Glycosylation of the beta 4 subunit is not required for its binding to the hSlo channel alpha  subunit. It also is not necessary for cell membrane targeting of the beta 4 subunit, as demonstrated by surface biotinylation experiments. However, the double glycosylation site mutant beta 4 (beta 4 N53A/N90A) protects the channel less against toxin blockade, as compared with the hSlo channel coexpressed with wild type beta 4 subunit. Taken together, these data show that the pore-forming alpha  subunit of the hSlo channel promotes N-linked glycosylation of its auxiliary beta 4 subunit, and this in turn influences the modulation of the channel by the beta 4 subunit.

* This work was supported by grants (to I. B. L.) from Millennium Pharmaceuticals and the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These two authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Neuroscience, University of Pennsylvania School of Medicine, 223 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104. E-mail:

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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