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J. Biol. Chem. 276 (46): 43239-43245

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

A Molecular Switch for Specific Stimulation of the BKCa Channel by cGMP and cAMP Kinase*

Xiao-Bo ZhouDagger , Claudia Arntz§, Simone Kamm§, Karin MotejlekDagger , Ulrike Sausbier§, Ge-Xin WangDagger , Peter Ruth§||, and Michael KorthDagger

From the Dagger  Abteilung Pharmakologie für Pharmazeuten, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg and § Institut für Pharmakologie und Toxikologie der Technischen Universität München, Biedersteinerstr. 29, D-80802 München Germany

The cGMP and the cAMP pathways control smooth muscle tone by regulation of BKCa (BK) channel activity. BK channels show considerable diversity and plasticity in their regulation by cyclic nucleotide-dependent protein kinases. The underlying molecular mechanisms are unclear but may involve expression of splice variants of the BK channel alpha  subunit. Three isoforms, BKA, BKB, and BKC, which were cloned from tracheal smooth muscle, differed only in their C terminus. When expressed in HEK293 cells, cGMP kinase (cGK) but not cAMP kinase (cAK) stimulated the activity of BKA and BKB by shifting the voltage dependence of the channel to more negative potentials. In contrast, BKC was exclusively stimulated by cAK. BKC lacks a C-terminal tandem phosphorylation motif for protein kinase C (PKC) with Ser1151 and Ser1154. Mutation of this motif in BKA switched channel regulation from cGK to cAK. Furthermore, inhibition of PKC in excised patches from cells expressing BKA abolished the stimulatory effect of cGK but allowed channel stimulation by cAK. cAK and cGK phosphorylated the channel at different sites. Thus, phosphorylation/dephosphorylation by PKC determines whether the BK channel is stimulated by cGK or cAK. The molecular mechanisms may be relevant for smooth muscle relaxation by cAMP and cGMP.

* This work was supported by Deutsche Forschungsgemeinschaft.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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AY033472 (BKA), AY033473 (BKB), and AY033474 (BKC).

|| To whom correspondence should be addressed. Tel.: 49-7071-2976781; Fax: 49-7071-292476; E-mail: peter.ruth@uni-tuebingen.de.

Contributed equally.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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