Divalent cations slow activation of EAG family K+ channels through direct binding to S4.
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.
Zhang
Xiaofei
X
Department of Cell Biology, Institute for Childhood and Neglected Diseases, The Scripps Research Institute, La Jolla, California 92037, USA.
Bursulaya
Badry
B
Lee
Christian C
CC
Chen
Bihan
B
Pivaroff
Kendra
K
Jegla
Timothy
T
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
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