×

Computing rates of Markov models of voltage-gated ion channels by inverting partial differential equations governing the probability density functions of the conducting and non-conducting states. (English) Zbl 1358.92046

Summary: Markov models are ubiquitously used to represent the function of single ion channels. However, solving the inverse problem to construct a Markov model of single channel dynamics from bilayer or patch-clamp recordings remains challenging, particularly for channels involving complex gating processes. Methods for solving the inverse problem are generally based on data from voltage clamp measurements. Here, we describe an alternative approach to this problem based on measurements of voltage traces. The voltage traces define probability density functions of the functional states of an ion channel. These probability density functions can also be computed by solving a deterministic system of partial differential equations. The inversion is based on tuning the rates of the Markov models used in the deterministic system of partial differential equations such that the solution mimics the properties of the probability density function gathered from (pseudo) experimental data as well as possible. The optimization is done by defining a cost function to measure the difference between the deterministic solution and the solution based on experimental data. By evoking the properties of this function, it is possible to infer whether the rates of the Markov model are identifiable by our method. We present applications to Markov model well-known from the literature.

MSC:

92C40 Biochemistry, molecular biology
92C10 Biomechanics
60J22 Computational methods in Markov chains
60J28 Applications of continuous-time Markov processes on discrete state spaces

Software:

QUB

References:

[1] Keener, J.; Sneyd, J., Mathematical Physiology (2009), Springer · Zbl 1273.92018
[2] Smith, G. D., Modeling the stochastic gating of ion channels, (Fall, C. P.; Marland, E. S.; Wagner, J. M.; Tyson, J. J., Computational Cell Biology. Computational Cell Biology, Interdisciplinary Applied Mathematics, vol. 20 (2002), Springer), 285-319 · Zbl 1010.92019
[3] Bressloff, P. C., Stochastic Processes in Cell Biology, vol. 41 (2014), Springer · Zbl 1402.92001
[4] Tveito, A.; Lines, G. T., Computing characterizations of drugs for ion channels and receptors using Markov models, vol. 111 (2016), Springer: Springer Heidelberg, Germany · Zbl 1342.92010
[5] Shelley, C.; Magleby, K. L., Linking exponential components to kinetic states in Markov models for single-channel gating, J. Gen. Physiol., 132, 2, 295-312 (2008)
[6] Siekmann, I.; Wagner II, L. E.; Yule, D.; Fox, C.; Bryant, D.; Crampin, E. J.; Sneyd, J., MCMC estimation of Markov models for ion channels, Biophys. J., 100, 8, 1919-1929 (2011)
[7] Siekmann, I.; Sneyd, J.; Crampin, E. J., MCMC can detect nonidentifiable models, Biophys. J., 103, 11, 2275-2286 (2012)
[8] Hines, K. E.; Middendorf, T. R.; Aldrich, R. W., Determination of parameter identifiability in nonlinear biophysical models: A Bayesian approach, J. Gen. Physiol., 143, 3, 401-416 (2014)
[9] Csanády, L., Statistical evaluation of ion-channel gating models based on distributions of log-likelihood ratios, Biophys. J., 90, 10, 3523-3545 (2006)
[10] Neher, E.; Sakmann, B., Single-channel currents recorded from membrane of denervated frog muscle fibres, Nature, 224 (2010)
[11] Sakmann, B.; Neher, E., Patch clamp techniques for studying ionic channels in excitable membranes, Ann. Rev. Physiol., 46, 1, 455-472 (1984)
[12] Colquhoun, D.; Hawkes, A. G., Relaxation and fluctuations of membrane currents that flow through drug-operated channels, Proc. R. Soc. Lond. Ser. B Biol. Sci., 199, 1135, 231-262 (1977)
[13] Colquhoun, D.; Hawkes, A. G., On the stochastic properties of bursts of single ion channel openings and of clusters of bursts, Philos. Trans. R. Soc. Lond. B, 300, 1-59 (1982)
[14] (Sakmann, B.; Neher, E., Single-Channel Recording (1995), Springer)
[15] Qin, F.; Auerbach, A.; Sachs, F., Estimating single-channel kinetic parameters from idealized patch-clamp data containing missed events, Biophys. J., 70, 264-280 (1996)
[16] Qin, F.; Auerbach, A.; Sachs, F., A direct optimization approach to hidden Markov modeling for single channel kinetics, Biophys. J., 79, 1915-1927 (2000)
[17] Nicolai, C.; Sachs, F., Solving ion channel kinetics with the QuB software, Biophys. Rev. Lett., 8, 3-4, 191-211 (2013)
[18] Ball, F. G.; Davies, S. S., Statistical inference for a two-state Markov model of a single ion channel, incorporating time interval omission, J. R. Stat. Soc. Ser. B (Methodol.), 57, 1, 269-287 (1995) · Zbl 0809.62076
[19] Rosales, R. A., Mcmc for hidden Markov models incorporating aggregation of states and filtering, Bull. Math. Biol., 66, 5, 1173-1199 (2004) · Zbl 1334.92148
[20] Gin, E.; Falcke, M.; Wagner, L. E.; Yule, D. I.; Sneyd, J., Markov chain Monte Carlo fitting of single-channel data from inositol trisphosphate receptors, J. Theor. Biol., 257, 3, 460-474 (2009) · Zbl 1400.92184
[21] Fredkin, D. R.; Rice, J. A., On aggregated Markov processes, J. Appl. Probab., 23, 1, 208-214 (1986) · Zbl 0589.60058
[22] Milescu, L. S.; Yamanishi, T.; Ptak, K.; Mogri, M. Z.; Smith, J. C., Real-time kinetic modeling of voltage-gated ion channels using dynamic clamp, Biophys. J., 95, 1, 66-87 (2008)
[23] Apostol, T. M., Calculus, vol. II (1969), Wiley · Zbl 0185.11402
[24] Fornberg, B., Generation of finite difference formulas on arbitrarily spaced grids, Math. Comput., 51, 184, 699-706 (1988) · Zbl 0701.65014
[25] Zhou, Q.; Bett, G. C.L.; Rasmusson, R. L., Markov models of use-dependence and reverse use-dependence during the mouse cardiac action potential, PLoS ONE, 7, 8, e42295 (2012)
This reference list is based on information provided by the publisher or from digital mathematics libraries. Its items are heuristically matched to zbMATH identifiers and may contain data conversion errors. In some cases that data have been complemented/enhanced by data from zbMATH Open. This attempts to reflect the references listed in the original paper as accurately as possible without claiming completeness or a perfect matching.