Abstract
The mechanism(s) of action of most commonly used pharmacological blockers of voltage-gated ion channels are well understood; however, this knowledge is rarely considered when interpreting experimental data. Effects of blockade are often assumed to be equivalent, regardless of the mechanism of the blocker involved. Using computer simulations, we demonstrate that this assumption may not always be correct. We simulate the blockade of a persistent sodium current (INaP), proposed to underlie rhythm generation in pre-Bötzinger complex (pre-BötC) respiratory neurons, via two distinct pharmacological mechanisms: (1) pore obstruction mediated by tetrodotoxin and (2) altered inactivation dynamics mediated by riluzole. The reported effects of experimental application of tetrodotoxin and riluzole in respiratory circuits are diverse and seemingly contradictory and have led to considerable debate within the field as to the specific role of INaP in respiratory circuits. The results of our simulations match a wide array of experimental data spanning from the level of isolated pre-BötC neurons to the level of the intact respiratory network and also generate a series of experimentally testable predictions. Specifically, in this study we: (1) provide a mechanistic explanation for seemingly contradictory experimental results from in vitro studies of INaP block, (2) show that the effects of INaP block in in vitro preparations are not necessarily equivalent to those in more intact preparations, (3) demonstrate and explain why riluzole application may fail to effectively block INaP in the intact respiratory network, and (4) derive the prediction that effective block of INaP by low concentration tetrodotoxin will stop respiratory rhythm generation in the intact respiratory network. These simulations support a critical role for INaP in respiratory rhythmogenesis in vivo and illustrate the importance of considering mechanism when interpreting and simulating data relating to pharmacological blockade.
Highlights
Pharmacological compounds that selectively block voltage-gated ion channels are a fundamental tool in neuroscience
We offer potential explanations for disparate findings observed in experiments on neural respiratory circuits and show that the experimental results are consistent with a key role for the persistent sodium current in respiratory rhythm generation
To illustrate the difference in effects that can arise through blockade of the same current with pharmacological agents acting through different biophysical mechanisms, we focused on the blockade of INaP via RZ and TTX in respiratory neurons of the pre-BotC
Summary
Pharmacological compounds that selectively block voltage-gated ion channels are a fundamental tool in neuroscience. The mechanisms of action for many of the most commonly used pharmaceutical blockers of voltage-gated ion channels are relatively well understood and fall into one of three mechanistic categories: (1) pore obstruction, (2) shift in activation/inactivation curves, or, less commonly, (3) alteration of ion selectivity [1, 2]. Despite this knowledge, the specific mechanisms of blockade are rarely considered when interpreting or simulating experimental data. We demonstrate ways that this assumption can break down, with different blockade mechanisms differentially impacting neuronal and circuit activity
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