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J. Biol. Chem., Vol. 279, Issue 2, 1003-1009, January 9, 2004

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The SK3 Subunit of Small Conductance Ca²⁺-activated K⁺ Channels Interacts with Both SK1 and SK2 Subunits in a Heterologous Expression System^*

Alan S. Monaghan, David C. H. Benton, Parmvir K. Bahia, Ramine Hosseini, Yousaf A. Shah, Dennis G. Haylett, and Guy W. J. Moss

From the Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom

The aim of this study was to determine whether functional heteromeric channels can be formed by co-assembly of rat SK3 (rSK3) potassium channel subunits with either SK1 or SK2 subunits. First, to determine whether rSK3 could co-assemble with rSK2 we created rSK3VK (an SK3 mutant insensitive to block by UCL 1848). When rSK3VK was co-expressed with rSK2 the resulting currents had an intermediate sensitivity to UCL 1848 (IC₅₀ of 5nM compared with 120 pM for rSK2 and >300 nM for rSK3VK), suggesting that rSK3 and rSK2 can form functional heteromeric channels. To detect co-assembly of SK3 with SK1, we initially used a dominant negative construct of the human SK1 subunit (hSK1YP). hSK1YP dramatically reduced the SK3 current, supporting the idea that SK3 and SK1 subunits also interact. To determine whether these assemblies were functional we created rSK3VF, an rSK3 mutant with an enhanced affinity for tetraethylammonium chloride (TEA) (IC₅₀ of 0.3 mM). Co-transfection of rSK3VF and hSK1 produced currents with a sensitivity to TEA not different from that of hSK1 alone (IC₅₀ 15 mM). These results suggest that hSK1 does not produce functional cell-surface assemblies with SK3. Antibody-staining experiments suggested that hSK1 may reduce the number of functional SK3 subunits reaching the cell surface. Additional experiments showed that co-expression of the rat SK1 gene with SK3 also dramatically suppressed SK current. The pharmacology of the residual current was consistent with that of homomeric SK3 assemblies. These results demonstrate interactions that cause changes in protein trafficking, cell surface expression, and channel pharmacology and strongly suggest heteromeric assembly of SK3 with the other SK channel subunits.

Received for publication, July 24, 2003 , and in revised form, October 8, 2003.

^* This work was supported by the Wellcome Trust and United Kingdom Medical Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a MRC/GSK collaborative research studentship.

To whom correspondence should be addressed: Dept. of Pharmacology, University College London, London WC1E 6BT, United Kingdom. E-mail: g.moss{at}ucl.ac.uk.

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