title: Conopeptide Vt3.1 preferentially inhibits BK potassium channels containing β4 subunits via electrostatic interactions.
abstract: BK channel β subunits (β1-β4) modulate the function of channels formed by slo1 subunits to produce tissue-specific phenotypes. The molecular mechanism of how the homologous β subunits differentially alter BK channel functions and the role of different BK channel functions in various physiologic processes remain unclear. By studying channels expressed in Xenopus laevis oocytes, we show a novel disulfide-cross-linked dimer conopeptide, Vt3.1 that preferentially inhibits BK channels containing the β4 subunit, which is most abundantly expressed in brain and important for neuronal functions. Vt3.1 inhibits the currents by a maximum of 71%, shifts the G-V relation by 45 mV approximately half-saturation concentrations, and alters both open and closed time of single channel activities, indicating that the toxin alters voltage dependence of the channel. Vt3.1 contains basic residues and inhibits voltage-dependent activation by electrostatic interactions with acidic residues in the extracellular loops of the slo1 and β4 subunits. These results suggest a large interaction surface between the slo1 subunit of BK channels and the β4 subunit, providing structural insight into the molecular interactions between slo1 and β4 subunits. The results also suggest that Vt3.1 is an excellent tool for studying β subunit modulation of BK channels and for understanding the physiological roles of BK channels in neurophysiology.
authors.affiliation: From the Institute of Protein Research, Tongji University, Shanghai 200092, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Shan
authors.initials: S
authors.lastname: Chang
authors.forename: Longjin
authors.initials: L
authors.lastname: Yang
authors.forename: Jingyi
authors.initials: J
authors.lastname: Shi
authors.forename: Kelli
authors.initials: K
authors.lastname: McFarland
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.forename: Alyssa
authors.initials: A
authors.lastname: Moller
authors.forename: Chunguang
authors.initials: C
authors.lastname: Wang
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Zou
authors.forename: Chengwu
authors.initials: C
authors.lastname: Chi
authors.forename: Jianmin
authors.initials: J
authors.lastname: Cui
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D020916:Conotoxins / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D015640:Ion Channel Gating / Q000187:drug effects; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D000596:Amino Acids; D020916:Conotoxins; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D026902:Potassium Channel Blockers; D021122:Protein Subunits
keywords: Activation; BK Channel; Conopeptide; Electrophysiology; Electrostatic Interaction; Molecular Modeling; Peptide Interactions; Potassium Channels; Toxins; β4 Subunit