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A single Markov-type kinetic model accounting for the macroscopic currents of all human voltage-gated sodium channel isoforms
KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsvetenskap och beräkningsteknik (CST).ORCID-id: 0000-0002-0550-0739
2017 (engelsk)Inngår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 13, nr 9, artikkel-id e1005737Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Modelling ionic channels represents a fundamental step towards developing biologically detailed neuron models. Until recently, the voltage-gated ion channels have been mainly modelled according to the formalism introduced by the seminal works of Hodgkin and Huxley (HH). However, following the continuing achievements in the biophysical and molecular comprehension of these pore-forming transmembrane proteins, the HH formalism turned out to carry limitations and inconsistencies in reproducing the ion-channels electrophysiological behaviour. At the same time, Markov-type kinetic models have been increasingly proven to successfully replicate both the electrophysiological and biophysical features of different ion channels. However, in order to model even the finest non-conducting molecular conformational change, they are often equipped with a considerable number of states and related transitions, which make them computationally heavy and less suitable for implementation in conductance-based neurons and large networks of those. In this purely modelling study we develop a Markov-type kinetic model for all human voltage-gated sodium channels (VGSCs). The model framework is detailed, unifying (i.e., it accounts for all ion-channel isoforms) and computationally efficient (i.e. with a minimal set of states and transitions). The electrophysiological data to be modelled are gathered from previously published studies on whole-cell patch-clamp experiments in mammalian cell lines heterologously expressing the human VGSC subtypes (from NaV1.1 to NaV1.9). By adopting a minimum sequence of states, and using the same state diagram for all the distinct isoforms, the model ensures the lightest computational load when used in neuron models and neural networks of increasing complexity. The transitions between the states are described by original ordinary differential equations, which represent the rate of the state transitions as a function of voltage (i.e., membrane potential). The kinetic model, developed in the NEURON simulation environment, appears to be the simplest and most parsimonious way for a detailed phenomenological description of the human VGSCs electrophysiological behaviour.

sted, utgiver, år, opplag, sider
Public Library of Science , 2017. Vol. 13, nr 9, artikkel-id e1005737
Emneord [en]
isoprotein, voltage gated sodium channel, biological model, biology, cell line, chemistry, computer simulation, human, kinetics, Markov chain, metabolism, physiology, procedures, Computational Biology, Humans, Markov Chains, Models, Neurological, Protein Isoforms, Voltage-Gated Sodium Channels
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Identifikatorer
URN: urn:nbn:se:kth:diva-216195DOI: 10.1371/journal.pcbi.1005737ISI: 000411981000029Scopus ID: 2-s2.0-85030469258OAI: oai:DiVA.org:kth-216195DiVA, id: diva2:1168182
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QC 20171220

Tilgjengelig fra: 2017-12-20 Laget: 2017-12-20 Sist oppdatert: 2018-01-13bibliografisk kontrollert

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