TY - JOUR
T1 - Mechanisms and models of cardiac sodium channel inactivation
AU - Mangold, Kathryn E.
AU - Brumback, Brittany D.
AU - Angsutararux, Paweorn
AU - Voelker, Taylor L.
AU - Zhu, Wandi
AU - Kang, Po Wei
AU - Moreno, Jonathan D.
AU - Silva, Jonathan R.
N1 - Publisher Copyright:
© 2017 Taylor & Francis.
PY - 2017/11/2
Y1 - 2017/11/2
N2 - Shortly after cardiac Na+ channels activate and initiate the action potential, inactivation ensues within milliseconds, attenuating the peak Na+ current, INa, and allowing the cell membrane to repolarize. A very limited number of Na+ channels that do not inactivate carry a persistent INa, or late INa. While late INa is only a small fraction of peak magnitude, it significantly prolongs ventricular action potential duration, which predisposes patients to arrhythmia. Here, we review our current understanding of inactivation mechanisms, their regulation, and how they have been modeled computationally. Based on this body of work, we conclude that inactivation and its connection to late INa would be best modeled with a “feet-on-the-door” approach where multiple channel components participate in determining inactivation and late INa. This model reflects experimental findings showing that perturbation of many channel locations can destabilize inactivation and cause pathological late INa.
AB - Shortly after cardiac Na+ channels activate and initiate the action potential, inactivation ensues within milliseconds, attenuating the peak Na+ current, INa, and allowing the cell membrane to repolarize. A very limited number of Na+ channels that do not inactivate carry a persistent INa, or late INa. While late INa is only a small fraction of peak magnitude, it significantly prolongs ventricular action potential duration, which predisposes patients to arrhythmia. Here, we review our current understanding of inactivation mechanisms, their regulation, and how they have been modeled computationally. Based on this body of work, we conclude that inactivation and its connection to late INa would be best modeled with a “feet-on-the-door” approach where multiple channel components participate in determining inactivation and late INa. This model reflects experimental findings showing that perturbation of many channel locations can destabilize inactivation and cause pathological late INa.
KW - computational models
KW - inherited arrhythmias
KW - late sodium current
KW - sodium channels
UR - http://www.scopus.com/inward/record.url?scp=85029671026&partnerID=8YFLogxK
U2 - 10.1080/19336950.2017.1369637
DO - 10.1080/19336950.2017.1369637
M3 - Review article
C2 - 28837385
AN - SCOPUS:85029671026
SN - 1933-6950
VL - 11
SP - 517
EP - 533
JO - Channels
JF - Channels
IS - 6
ER -