Abstract
Type-II ryanodine receptor channels (RYRs) play a fundamental role
in intracellular Ca$^2+$ dynamics in heart. The processes of
activation, inactivation, and regulation of these channels have been
the subject of intensive research and the focus of recent debates.
Typically, approaches to understand these processes involve statistical
analysis of single RYRs, involving signal restoration, model estimation,
and selection. These tasks are usually performed by following rather
phenomenological criteria that turn models into self-fulfilling prophecies.
Here, a thorough statistical treatment is applied by modeling single
RYRs using aggregated hidden Markov models. Inferences are made using
Bayesian statistics and stochastic search methods known as Markov
chain Monte Carlo. These methods allow extension of the temporal
resolution of the analysis far beyond the limits of previous approaches
and provide a direct measure of the uncertainties associated with
every estimation step, together with a direct assessment of why and
where a particular model fails. Analyses of single RYRs at several
Ca$^2+$ concentrations are made by considering 16 models, some
of them previously reported in the literature. Results clearly show
that single RYRs have Ca$^2+$-dependent gating modes. Moreover,
our results demonstrate that single RYRs responding to a sudden change
in Ca$^2+$ display adaptation kinetics. Interestingly, best ranked
models predict microscopic reversibility when monovalent cations
are used as the main permeating species. Finally, the extended bandwidth
revealed the existence of novel fast buzz-mode at low Ca$^2+$
concentrations.
- 15111644
- algorithms,
- and
- animals,
- b,
- bayes
- biological,
- calcium
- calcium,
- cardiac,
- carlo
- cells,
- chains,
- channel
- channel,
- channels,
- comparative
- computer
- cultured,
- data
- dogs,
- gating,
- gov't,
- homeostasis,
- interpretation,
- iological,
- ion
- markov
- membrane
- method,
- microsomes,
- models,
- monte
- myocytes,
- non-u.s.
- of
- p.h.s.,
- patch-clamp
- potentials,
- processes,
- receptor
- release
- reproducibility
- research
- results,
- ryanodine
- sensitivity
- signaling,
- simulation,
- specificity,
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