title: Subconductance gating and voltage sensitivity of sarcoplasmic reticulum K(+) channels: a modeling approach.
abstract: Sarcoplasmic reticulum (SR) K(+) channels are voltage-regulated channels that are thought to be actively gating when the membrane potential across the SR is close to zero as is expected physiologically. A characteristic of SR K(+) channels is that they gate to subconductance open states but the relevance of the subconductance events and their contribution to the overall current flowing through the channels at physiological membrane potentials is not known. We have investigated the relationship between subconductance and full conductance openings and developed kinetic models to describe the voltage sensitivity of channel gating. Because there may be two subtypes of SR K(+) channels (TRIC-A and TRIC-B) present in most tissues, to conduct our study on a homogeneous population of SR K(+) channels, we incorporated SR vesicles derived from Tric-a knockout mice into artificial membranes to examine the remaining SR K(+) channel (TRIC-B) function. The channels displayed very low open probability (Po) at negative potentials (≤0 mV) and opened predominantly to subconductance open states. Positive holding potentials primarily increased the frequency of subconductance state openings and thereby increased the number of subsequent transitions into the full open state, although a slowing of transitions back to the sublevels was also important. We investigated whether the subconductance gating could arise as an artifact of incomplete resolution of rapid transitions between full open and closed states; however, we were not able to produce a model that could fit the data as well as one that included multiple distinct current amplitudes. Our results suggest that the apparent subconductance openings will provide most of the K(+) flux when the SR membrane potential is close to zero. The relative contribution played by openings to the full open state would increase if negative charge developed within the SR thus increasing the capacity of the channel to compensate for ionic imbalances.
authors.affiliation: Bristol Centre for Complexity Sciences, University of Bristol, Bristol, United Kingdom; Department of Engineering Mathematics, University of Bristol, Bristol, United Kingdom. Electronic address: antoni.matyjaszkiewicz@bristol.ac.uk.
authors.forename: Antoni
authors.initials: A
authors.lastname: Matyjaszkiewicz
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Elisa
authors.initials: E
authors.lastname: Venturi
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Fiona
authors.initials: F
authors.lastname: O'Brien
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshidahonmachi, Sakyo Ward, Kyoto, Japan.
authors.forename: Tsunaki
authors.initials: T
authors.lastname: Iida
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshidahonmachi, Sakyo Ward, Kyoto, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Nishi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshidahonmachi, Sakyo Ward, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeshima
authors.affiliation: College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, United Kingdom.
authors.forename: Krasimira
authors.initials: K
authors.lastname: Tsaneva-Atanasova
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom. Electronic address: rebecca.sitsapesan@pharm.ox.ac.uk.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sitsapesan
mesh_terms: D000818:Animals; D003198:Computer Simulation; D007473:Ion Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008051:Lipid Bilayers / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology*; D018345:Mice, Knockout; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010714:Phosphatidylethanolamines; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: D007473:Ion Channels; D008051:Lipid Bilayers; D010714:Phosphatidylethanolamines; C522221:TRIC-A protein, mouse; C522222:TRIC-B protein, mouse; C483858:phosphatidylethanolamine