Tethering chemistry and K+ channels.
Voltage-gated K+ channels are dynamic macromolecular machines that open and close in response to changes in membrane potential. These multisubunit membrane-embedded proteins are responsible for governing neuronal excitability, maintaining cardiac rhythmicity, and regulating epithelial electrolyte homeostasis. High resolution crystal structures have provided snapshots of K+ channels caught in different states with incriminating molecular detail. Nonetheless, the connection between these static images and the specific trajectories of K+ channel movements is still being resolved by biochemical experimentation. Electrophysiological recordings in the presence of chemical modifying reagents have been a staple in ion channel structure/function studies during both the pre- and post-crystal structure eras. Small molecule tethering agents (chemoselective electrophiles linked to ligands) have proven to be particularly useful tools for defining the architecture and motions of K+ channels. This Minireview examines the synthesis and utilization of chemical tethering agents to probe and manipulate the assembly, structure, function, and molecular movements of voltage-gated K+ channel protein complexes.
Morin
Trevor J
TJ
Department of Biochemistry and Molecular Pharmacology, Programs in Neuroscience and Chemical Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605-2324.
Kobertz
William R
WR
Department of Biochemistry and Molecular Pharmacology, Programs in Neuroscience and Chemical Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605-2324. Electronic address: william.kobertz@umassmed.edu.
D000818:Animals; D001671:Biochemistry / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D003545:Cysteine / Q000737:chemistry; D004594:Electrophysiology / Q000379:methods; D006801:Humans; D015640:Ion Channel Gating; D008024:Ligands; D008564:Membrane Potentials; D008954:Models, Biological; D008956:Models, Chemical; D008968:Molecular Conformation; D009474:Neurons / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D011487:Protein Conformation
D008024:Ligands; D024642:Potassium Channels, Voltage-Gated; D003545:Cysteine