Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Inhalational anaesthetics and n-alcohols share a site of action in the neuronal Shaw2 Kv channel.
Bhattacharji A
,
Klett N
,
Go RC
,
Covarrubias M
.
???displayArticle.abstract???
Neuronal ion channels are key targets of general anaesthetics and alcohol, and binding of these drugs to pre-existing and relatively specific sites is thought to alter channel gating. However, the underlying molecular mechanisms of this action are still poorly understood. Here, we investigated the neuronal Shaw2 voltage-gated K(+) (K(v)) channel to ask whether the inhalational anaesthetic halothane and n-alcohols share a binding site near the activation gate of the channel.Focusing on activation gate mutations that affect channel modulation by n-alcohols, we investigated n-alcohol-sensitive and n-alcohol-resistant K(v) channels heterologously expressed in Xenopus oocytes to probe the functional modulation by externally applied halothane using two-electrode voltage clamping and a gas-tight perfusion system.Shaw2 K(v) channels are reversibly inhibited by halothane in a dose-dependent and saturable manner (K(0.5)= 400 microM; n(H)= 1.2). Also, discrete mutations in the channel's S4S5 linker are sufficient to reduce or confer inhibition by halothane (Shaw2-T330L and K(v)3.4-G371I/T378A respectively). Furthermore, a point mutation in the S6 segment of Shaw2 (P410A) converted the halothane-induced inhibition into halothane-induced potentiation. Lastly, the inhibition resulting from the co-application of n-butanol and halothane is consistent with the presence of overlapping binding sites for these drugs and weak binding cooperativity.These observations strongly support a molecular model of a general anaesthetic binding site in the Shaw2 K(v) channel. This site may involve the amphiphilic interface between the S4S5 linker and the S6 segment, which plays a pivotal role in K(v) channel activation.
Alexander,
Guide to Receptors and Channels (GRAC), 3rd edition.
2008, Pubmed
Alexander,
Guide to Receptors and Channels (GRAC), 3rd edition.
2008,
Pubmed
Bhattacharji,
The concerted contribution of the S4-S5 linker and the S6 segment to the modulation of a Kv channel by 1-alkanols.
2006,
Pubmed
,
Xenbase
Bucci,
Effect of n-alcohols on the structure and stability of the Drosophila odorant binding protein LUSH.
2006,
Pubmed
Chen,
Suppression of ih contributes to propofol-induced inhibition of mouse cortical pyramidal neurons.
2005,
Pubmed
,
Xenbase
Chen,
Subunit-specific effects of isoflurane on neuronal Ih in HCN1 knockout mice.
2009,
Pubmed
Chen,
The S4-S5 linker couples voltage sensing and activation of pacemaker channels.
2001,
Pubmed
,
Xenbase
Covarrubias,
Ethanol selectively blocks a noninactivating K+ current expressed in Xenopus oocytes.
1993,
Pubmed
,
Xenbase
Covarrubias,
Alcohols inhibit a cloned potassium channel at a discrete saturable site. Insights into the molecular basis of general anesthesia.
1995,
Pubmed
,
Xenbase
Dilger,
The effects of general anaesthetics on ligand-gated ion channels.
2002,
Pubmed
Eckenhoff,
Molecular interactions between inhaled anesthetics and proteins.
1997,
Pubmed
Forman,
General anesthetics and molecular mechanisms of unconsciousness.
2008,
Pubmed
Franks,
Molecular targets underlying general anaesthesia.
2006,
Pubmed
Franks,
General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal.
2008,
Pubmed
Franks,
Molecular and cellular mechanisms of general anaesthesia.
1994,
Pubmed
Harris,
Ethanol's molecular targets.
2008,
Pubmed
Harris,
General anesthetic action at an internal protein site involving the S4-S5 cytoplasmic loop of a neuronal K(+) channel.
2000,
Pubmed
,
Xenbase
Harris,
Allosteric modulation of a neuronal K+ channel by 1-alkanols is linked to a key residue in the activation gate.
2003,
Pubmed
,
Xenbase
Hemmings,
Emerging molecular mechanisms of general anesthetic action.
2005,
Pubmed
Horishita,
n-Alcohols inhibit voltage-gated Na+ channels expressed in Xenopus oocytes.
2008,
Pubmed
,
Xenbase
Jerng,
Inactivation gating of Kv4 potassium channels: molecular interactions involving the inner vestibule of the pore.
1999,
Pubmed
,
Xenbase
Kruse,
Structure of a specific alcohol-binding site defined by the odorant binding protein LUSH from Drosophila melanogaster.
2003,
Pubmed
Labro,
Kv channel gating requires a compatible S4-S5 linker and bottom part of S6, constrained by non-interacting residues.
2008,
Pubmed
Liu,
Structural basis for high-affinity volatile anesthetic binding in a natural 4-helix bundle protein.
2005,
Pubmed
Long,
Voltage sensor of Kv1.2: structural basis of electromechanical coupling.
2005,
Pubmed
Long,
Crystal structure of a mammalian voltage-dependent Shaker family K+ channel.
2005,
Pubmed
Long,
Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment.
2007,
Pubmed
Lu,
Coupling between voltage sensors and activation gate in voltage-gated K+ channels.
2002,
Pubmed
,
Xenbase
McPhee,
A critical role for the S4-S5 intracellular loop in domain IV of the sodium channel alpha-subunit in fast inactivation.
1998,
Pubmed
,
Xenbase
Prole,
Reversal of HCN channel voltage dependence via bridging of the S4-S5 linker and Post-S6.
2006,
Pubmed
Shahidullah,
Molecular features of an alcohol binding site in a neuronal potassium channel.
2003,
Pubmed
,
Xenbase
Shiraishi,
Effects of alcohols and anesthetics on recombinant voltage-gated Na+ channels.
2004,
Pubmed
,
Xenbase
Strzalka,
Mechanism of interaction between the general anesthetic halothane and a model ion channel protein, I: Structural investigations via X-ray reflectivity from Langmuir monolayers.
2009,
Pubmed
Thode,
The role of multiple hydrogen-bonding groups in specific alcohol binding sites in proteins: insights from structural studies of LUSH.
2008,
Pubmed
Tristani-Firouzi,
Interactions between S4-S5 linker and S6 transmembrane domain modulate gating of HERG K+ channels.
2002,
Pubmed
,
Xenbase
Urban,
The site of anesthetic action.
2008,
Pubmed
Vedula,
A unitary anesthetic binding site at high resolution.
2009,
Pubmed
Ying,
Propofol block of I(h) contributes to the suppression of neuronal excitability and rhythmic burst firing in thalamocortical neurons.
2006,
Pubmed
