title: Pore-forming segments in voltage-gated chloride channels.
abstract: The ability to differentiate between ions is a property of ion channels that is crucial for their biological functions. However, the fundamental structural features that define anion selectivity and distinguish anion-permeable from cation-permeable channels are poorly understood. Voltage-gated chloride (Cl-) channels belonging to the ClC family are ubiquitous and have been predicted to play important roles in many diverse physiological and pathophysiological processes. We have identified regions of a human skeletal muscle ClC isoform that contribute to formation of its anion-selective conduction pathway. A core structural element (P1 region) of the ClC channel pore spans an accessibility barrier between the internal and external milieu, and contains an evolutionarily conserved sequence motif: GKxGPxxH. Neighbouring sequences in the third and fifth transmembrane segments also contribute to isoform-specific differences in anion selectivity. The conserved motif in the Cl- channel P1 region may constitute a 'signature' sequence for an anion-selective ion pore by analogy with the homologous GYG sequence that is essential for selectivity in voltage-gated potassium ion (K+) channel pores.
authors.affiliation: Department of Medicine (Nephrology), Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2372, USA.
authors.forename: C
authors.initials: C
authors.lastname: Fahlke
authors.forename: H T
authors.initials: HT
authors.lastname: Yu
authors.forename: C L
authors.initials: CL
authors.lastname: Beck
authors.forename: T H
authors.initials: TH
authors.lastname: Rhodes
authors.forename: A L
authors.initials: AL
authors.lastname: George
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002460:Cell Line; D018118:Chloride Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017124:Conserved Sequence; D006801:Humans; D007202:Indicators and Reagents; D015640:Ion Channel Gating; D008698:Mesylates / Q000494:pharmacology; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques
chemical_list: D018118:Chloride Channels; D007202:Indicators and Reagents; D008698:Mesylates