Radhakrishnan Gnanasambandam, Morten S. Nielsen, Christopher Nicolai, Frederick Sachs, Johannes P. Hofgaard, Jakob K. Dreyer
Abstract
Researchers can investigate the mechanistic and molecular basis of many physiological phenomena in cells by analyzing the fundamental properties of single ion channels. These analyses entail recording single channel currents and measuring current amplitudes and transition rates between conductance states. Since most electrophysiological recordings contain noise, the data analysis can proceed by idealizing the recordings to isolate the true currents from the noise. This de-noising can be accomplished with threshold crossing algorithms and Hidden Markov Models, but such procedures generally depend on inputs and supervision by the user, thus requiring some prior knowledge of underlying processes. Channels with unknown gating and/or functional sub-states and the presence in the recording of currents from uncorrelated background channels present substantial challenges to such analyses. Here we describe and characterize an idealization algorithm based on Rissanen's Minimum Description Length (MDL) Principle. This method uses minimal assumptions and idealizes ion channel recordings without requiring a detailed user input or a priori assumptions about channel conductance and kinetics. Furthermore, we demonstrate that correlation analysis of conductance steps can resolve properties of single ion channels in recordings contaminated by signals from multiple channels. We first validated our methods on simulated data defined with a range of different signal-to-noise levels, and then showed that our algorithm can recover channel currents and their substates from recordings with multiple channels, even under conditions of high noise. We then tested the MDL algorithm on real experimental data from human PIEZO1 channels and found that our method revealed the presence of substates with alternate conductances.
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