title: Molecular mechanism of pharmacological activation of BK channels.
abstract: Large-conductance voltage- and Ca(2+)-activated K(+) (Slo1 BK) channels serve numerous cellular functions, and their dysregulation is implicated in various diseases. Drugs activating BK channels therefore bear substantial therapeutic potential, but their deployment has been hindered in part because the mode of action remains obscure. Here we provide mechanistic insight into how the dehydroabietic acid derivative Cym04 activates BK channels. As a representative of NS1619-like BK openers, Cym04 reversibly left-shifts the half-activation voltage of Slo1 BK channels. Using an established allosteric BK gating model, the Cym04 effect can be simulated by a shift of the voltage sensor and the ion conduction gate equilibria toward the activated and open state, respectively. BK activation by Cym04 occurs in a splice variant-specific manner; it does not occur in such Slo1 BK channels using an alternative neuronal exon 9, which codes for the linker connecting the transmembrane segment S6 and the cytosolic RCK1 domain--the S6/RCK linker. In addition, Cym04 does not affect Slo1 BK channels with a two-residue deletion within this linker. Mutagenesis and model-based gating analysis revealed that BK openers, such as Cym04 and NS1619 but not mallotoxin, activate BK channels by functionally interacting with the S6/RCK linker, mimicking site-specific shortening of this purported passive spring, which transmits force from the cytosolic gating ring structure to open the channel's gate.
authors.affiliation: Center for Molecular Biomedicine, Department of Biophysics,  Friedrich Schiller University Jena and Jena University Hospital, D-07745 Jena,  Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Gessner
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Cui
authors.forename: Yuko
authors.initials: Y
authors.lastname: Otani
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohwada
authors.forename: Malle
authors.initials: M
authors.lastname: Soom
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hoshi
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Heinemann
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism
chemical_list: D045784:Abietanes; C571736:Cym04; C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; C013913:dehydroabietic acid; D011188:Potassium