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Article: Non-equilibrium behavior of HCN channels: Insights into the role of HCN channels in native and engineered pacemakers

TitleNon-equilibrium behavior of HCN channels: Insights into the role of HCN channels in native and engineered pacemakers
Authors
Issue Date2005
PublisherOxford University Press. The Journal's web site is located at http://cardiovascres.oxfordjournals.org
Citation
Cardiovascular Research, 2005, v. 67 n. 2, p. 263-273 How to Cite?
AbstractObjective: If, encoded by the hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channel gene family, modulates cardiac pacing. During cardiac pacing, changes in membrane potential are rapid, preventing the very slow HCN channels from reaching equilibrium. Here, we examined the properties of HCN channels under non-equilibrium conditions to shed insight into how different HCN isoforms contribute to cardiac pacing. Methods and results: HCN1, 2 and 4 channels were heterologously expressed in Xenopus laevis oocytes or mammalian Cos7 cells and subjected to voltage clamp. We found that HCN1 channel activation (V1/2) depended strongly on the holding potential (VH) for short (100 ms; V1/2 = - 118 mV, - 78 mV and - 19 mV for VH = + 70, - 75 and - 140 mV, respectively, in Xenopus oocytes) but not long (300-ms) test-pulses, hinting that shifts of V 1/2 under non-equilibrium conditions may alter the impact of I f in different phases of the cardiac circle. Consistent with this notion, when a train of SA nodal-like action potentials was applied in voltage-clamp experiments, HCN1 exhibited pronounced current-voltage (IV)-hysteresis. Using computational modeling, we demonstrate that the intrinsically sluggish HCN1 activation kinetics underlie their IV-hysteretic behavior and do not hinder the ability to modulate cardiac pacing. By contrast, HCN4 did not exhibit IV-hysteresis. This difference can be attributed to the relatively large activation time constant and markedly delayed onsets of time-dependent HCN4 currents. Indeed, HCN2 channels, which have intermediate activation time constants and delays, displayed and intermediate hysteretic phenotype. Conclusion: We conclude that non-equilibrium properties of HCN channels contribute to cardiac pacing. These results provide insight for tuning the firing rate of endogenous and induced pacemakers using engineered HCN constructs with distinct gating phenotypes. © 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/91422
ISSN
2015 Impact Factor: 5.465
2015 SCImago Journal Rankings: 2.897
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorAzene, EMen_HK
dc.contributor.authorXue, Ten_HK
dc.contributor.authorMarbán, Een_HK
dc.contributor.authorTomaselli, GFen_HK
dc.contributor.authorLi, RAen_HK
dc.date.accessioned2010-09-17T10:19:07Z-
dc.date.available2010-09-17T10:19:07Z-
dc.date.issued2005en_HK
dc.identifier.citationCardiovascular Research, 2005, v. 67 n. 2, p. 263-273en_HK
dc.identifier.issn0008-6363en_HK
dc.identifier.urihttp://hdl.handle.net/10722/91422-
dc.description.abstractObjective: If, encoded by the hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channel gene family, modulates cardiac pacing. During cardiac pacing, changes in membrane potential are rapid, preventing the very slow HCN channels from reaching equilibrium. Here, we examined the properties of HCN channels under non-equilibrium conditions to shed insight into how different HCN isoforms contribute to cardiac pacing. Methods and results: HCN1, 2 and 4 channels were heterologously expressed in Xenopus laevis oocytes or mammalian Cos7 cells and subjected to voltage clamp. We found that HCN1 channel activation (V1/2) depended strongly on the holding potential (VH) for short (100 ms; V1/2 = - 118 mV, - 78 mV and - 19 mV for VH = + 70, - 75 and - 140 mV, respectively, in Xenopus oocytes) but not long (300-ms) test-pulses, hinting that shifts of V 1/2 under non-equilibrium conditions may alter the impact of I f in different phases of the cardiac circle. Consistent with this notion, when a train of SA nodal-like action potentials was applied in voltage-clamp experiments, HCN1 exhibited pronounced current-voltage (IV)-hysteresis. Using computational modeling, we demonstrate that the intrinsically sluggish HCN1 activation kinetics underlie their IV-hysteretic behavior and do not hinder the ability to modulate cardiac pacing. By contrast, HCN4 did not exhibit IV-hysteresis. This difference can be attributed to the relatively large activation time constant and markedly delayed onsets of time-dependent HCN4 currents. Indeed, HCN2 channels, which have intermediate activation time constants and delays, displayed and intermediate hysteretic phenotype. Conclusion: We conclude that non-equilibrium properties of HCN channels contribute to cardiac pacing. These results provide insight for tuning the firing rate of endogenous and induced pacemakers using engineered HCN constructs with distinct gating phenotypes. © 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.en_HK
dc.languageengen_HK
dc.publisherOxford University Press. The Journal's web site is located at http://cardiovascres.oxfordjournals.orgen_HK
dc.relation.ispartofCardiovascular Researchen_HK
dc.subject.meshAction Potentialsen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshCOS Cellsen_HK
dc.subject.meshCercopithecus aethiopsen_HK
dc.subject.meshComputer Simulationen_HK
dc.subject.meshCyclic Nucleotide-Gated Cation Channelsen_HK
dc.subject.meshElasticityen_HK
dc.subject.meshFemaleen_HK
dc.subject.meshHeart Conduction System - physiologyen_HK
dc.subject.meshHumansen_HK
dc.subject.meshIon Channel Gating - physiologyen_HK
dc.subject.meshIon Channels - genetics - metabolismen_HK
dc.subject.meshModels, Cardiovascularen_HK
dc.subject.meshMuscle Proteins - genetics - metabolismen_HK
dc.subject.meshOocytesen_HK
dc.subject.meshPatch-Clamp Techniquesen_HK
dc.subject.meshPotassium Channelsen_HK
dc.subject.meshProtein Isoforms - genetics - metabolismen_HK
dc.subject.meshXenopusen_HK
dc.titleNon-equilibrium behavior of HCN channels: Insights into the role of HCN channels in native and engineered pacemakersen_HK
dc.typeArticleen_HK
dc.identifier.emailLi, RA:ronaldli@hkucc.hku.hken_HK
dc.identifier.authorityLi, RA=rp01352en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1016/j.cardiores.2005.03.006en_HK
dc.identifier.pmid16005302en_HK
dc.identifier.scopuseid_2-s2.0-21744440389en_HK
dc.identifier.hkuros183063-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-21744440389&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume67en_HK
dc.identifier.issue2en_HK
dc.identifier.spage263en_HK
dc.identifier.epage273en_HK
dc.identifier.isiWOS:000230691000014-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridAzene, EM=6602472909en_HK
dc.identifier.scopusauthoridXue, T=7005064190en_HK
dc.identifier.scopusauthoridMarbán, E=8075977300en_HK
dc.identifier.scopusauthoridTomaselli, GF=7005223451en_HK
dc.identifier.scopusauthoridLi, RA=7404724466en_HK
dc.identifier.citeulike267338-

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