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Molecular Coupling of S4 to a K+ Channel's Slow Inactivation Gate

Journal Article · · Journal of General Physiology
 [1];  [2]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Biosciences Division. Dept. of Molecular and Cell Biology; DOE/OSTI
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Biosciences Division. Dept. of Molecular and Cell Biology
The mechanism by which physiological signals regulate the conformation of molecular gates that open and close ion channels is poorly understood. Voltage clamp fluorometry was used to ask how the voltage-sensing S4 transmembrane domain is coupled to the slow inactivation gate in the pore domain of the Shaker K+ channel. Fluorophores attached at several sites in S4 indicate that the voltage-sensing rearrangements are followed by an additional inactivation motion. Fluorophores attached at the perimeter of the pore domain indicate that the inactivation rearrangement projects from the selectivity filter out to the interface with the voltage-sensing domain. Some of the pore domain sites also sense activation, and this appears to be due to a direct interaction with S4 based on the finding that S4 comes into close enough proximity to the pore domain for a pore mutation to alter the nanoenvironment of an S4-attached fluorophore. We propose that activation produces an S4–pore domain interaction that disrupts a bond between the S4 contact site on the pore domain and the outer end of S6. Our results indicate that this bond holds the slow inactivation gate open and, therefore, we propose that this S4-induced bond disruption triggers inactivation.
Research Organization:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1625205
Journal Information:
Journal of General Physiology, Journal Name: Journal of General Physiology Journal Issue: 5 Vol. 116; ISSN 0022-1295
Publisher:
Rockefeller University PressCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (42)

Molecular Determinants of U-Type Inactivation in Kv2.1 Channels journal August 2011
H Bonding at the Helix-Bundle Crossing Controls Gating in Kir Potassium Channels journal August 2007
Mechanism of Cd2+ Coordination during Slow Inactivation in Potassium Channels journal August 2012
Modulation of Kv1.5 Potassium Channel Gating by Extracellular Zinc journal July 2001
A Single Residue Differentiates between Human Cardiac and Skeletal Muscle Na+ Channel Slow Inactivation journal May 2001
Stretch-Activation and Stretch-Inactivation of Shaker-IR, a Voltage-Gated K+ Channel journal June 2001
Effect of External pH on Activation of the Kv1.5 Potassium Channel journal January 2003
Pore Helices Play a Dynamic Role as Integrators of Domain Motion during Kv11.1 Channel Inactivation Gating journal April 2013
S4 Charges Move Close to Residues in the Pore Domain during Activation in a K Channel journal July 2001
Altered State Dependence of C-Type Inactivation in the Long and Short Forms of Human Kv1.5 journal August 2001
Movement and Crevices Around a Sodium Channel S3 Segment journal August 2002
The Search Is on for the Voltage Sensor-to-gate Coupling journal September 2002
Molecular Models of Voltage Sensing journal September 2002
Membrane Tension Accelerates Rate-limiting Voltage-dependent Activation and Slow Inactivation Steps in a Shaker Channel journal January 2004
Coupling Interactions between Voltage Sensors of the Sodium Channel as Revealed by Site-specific Measurements journal February 2004
Influence of Permeant Ions on Voltage Sensor Function in the Kv2.1 Potassium Channel journal March 2004
External Barium Affects the Gating of KCNQ1 Potassium Channels and Produces a Pore Block via Two Discrete Sites journal June 2004
A Direct Demonstration of Closed-State Inactivation of K+ Channels at Low pH journal April 2007
And Yet It Moves: Conformational States of the Ca2+ Channel Pore journal May 2007
Tl+-induced μs Gating of Current Indicates Instability of the MaxiK Selectivity Filter as Caused by Ion/Pore Interaction journal March 2008
Voltage Clamp Fluorimetry Reveals a Novel Outer Pore Instability in a Mammalian Voltage-gated Potassium Channel journal July 2008
A single charged voltage sensor is capable of gating the Shaker K+ channel journal April 2009
Molecular endpoints of Ca2+/calmodulin- and voltage-dependent inactivation of Cav1.3 channels journal February 2010
Voltage-dependent inactivation gating at the selectivity filter of the MthK K+ channel journal October 2010
The contribution of voltage clamp fluorometry to the understanding of channel and transporter mechanisms journal August 2019
Mechanosensitive Gating of Kv Channels journal February 2015
The Pore, not Cytoplasmic Domains, Underlies Inactivation in a Prokaryotic Sodium Channel journal July 2005
Dual Stretch Responses of mHCN2 Pacemaker Channels: Accelerated Activation, Accelerated Deactivation journal March 2007
An Inactivation Gate in the Selectivity Filter of KCNQ1 Potassium Channels journal December 2007
Voltage Sensor Inactivation in Potassium Channels journal January 2012
Hydrogen bonds as molecular timers for slow inactivation in voltage-gated potassium channels journal December 2013
Drug block of the hERG potassium channel: Insight from modeling journal April 2007
Voltage-Dependent Inactivation Gating at the Selectivity Filter of the MthK K+ channel journal February 2011
Exploring Structural Dynamics of a Membrane Protein by Combining Bioorthogonal Chemistry and Cysteine Mutagenesis journal February 2020
A glimpse into the C-type-inactivated state for a Potassium Channel journal October 2017
Regional Specificity of Human ether-a'-go-go-related Gene Channel Activation and Inactivation Gating journal February 2005
A gating charge interaction required for late slow inactivation of the bacterial sodium channel NavAb journal August 2013
Modulation of homomeric and heteromeric kcnq1 channels by external acidification journal December 2002
Separation of P/C- and U-type inactivation pathways in Kv1.5 potassium channels: Multiple inactivation pathways in Kv1.5 journal September 2005
Mechanisms of closed-state inactivation in voltage-gated ion channels: Inactivation in voltage-gated ion channels journal January 2011
Shab K + channel slow inactivation: A test for U-type inactivation and a hypothesis regarding K + -facilitated inactivation mechanisms journal March 2013
Exploring structural dynamics of a membrane protein by combining bioorthogonal chemistry and cysteine mutagenesis journal November 2019

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