title: Divalent cations slow activation of EAG family K+ channels through direct binding to S4.
abstract: Voltage-gated K+ channels share a common voltage sensor domain (VSD) consisting of four transmembrane helices, including a highly mobile S4 helix that contains the major gating charges. Activation of ether-a-go-go (EAG) family K+ channels is sensitive to external divalent cations. We show here that divalent cations slow the activation rate of two EAG family channels (Kv12.1 and Kv10.2) by forming a bridge between a residue in the S4 helix and acidic residues in S2. Histidine 328 in the S4 of Kv12.1 favors binding of Zn2+ and Cd2+, whereas the homologous residue Serine 321 in Kv10.2 contributes to effects of Mg2+ and Ni2+. This novel finding provides structural constraints for the position of transmembrane VSD helices in closed, ion-bound EAG family channels. Homology models of Kv12.1 and Kv10.2 VSD structures based on a closed-state model of the Shaker family K+ channel Kv1.2 match these constraints. Our results suggest close conformational conservation between closed EAG and Shaker family channels, despite large differences in voltage sensitivity, activation rates, and activation thresholds.
authors: Department of Cell Biology, Institute for Childhood and Neglected Diseases, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Xiaofei
authors: X
authors: Zhang
authors: Badry
authors: B
authors: Bursulaya
authors: Christian C
authors: CC
authors: Lee
authors: Bihan
authors: B
authors: Chen
authors: Kendra
authors: K
authors: Pivaroff
authors: Timothy
authors: T
authors: Jegla
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002104:Cadmium / Q000378:metabolism; D002413:Cations, Divalent / Q000378:metabolism*; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051663:Kv1.2 Potassium Channel / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009532:Nickel / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D014981:Xenopus; D015032:Zinc / Q000378:metabolism
chemical_list: D002413:Cations, Divalent; D051638:Ether-A-Go-Go Potassium Channels; D051663:Kv1.2 Potassium Channel; C544139:Kv10.2 potassium channel, mouse; C544138:Kv12.1 potassium channel, mouse; D002104:Cadmium; D009532:Nickel; D008274:Magnesium; D015032:Zinc