Model Status

This CellML model still contains the reaction element. We have been unable to recode this model to remove the reaction element because the published paper does not contain a complete, quantitative model. Therefore this CellML model is a purely qualitative model it and contains no mathematical description of the pathways defined. All the rates and concentrations have been set to 1.0.

Model Structure

More than twenty different mutations in the alpha-subunit of the adult skeletal muscle Na⁺ channel have been identified. These mutations cause several heritable muscle diseases such as myotonia and periodic paralysis. The antiarrhythmic drug mexiletine is clinically used to reduce or prevent myotonia. It achieves this effect by blocking voltage-gated Na⁺ channels in a state-dependent manner. Resting channels at hyperpolarised potentials have a low affinity for the drug, but the affinity of depolarised channels is 20 to 100 times greater than this.

In their 2001 study, Masanori Takahashi and Stephen Cannon focused on the state-dependent mexiletine block for disease-associated mutations of the Na⁺ channel of mature human skeletal muscle cells. Experimental work revealed that the mutations had relatively little effect on the affinity of the Na⁺ channels for the drug mexiletine. They then performed model simulations with a modulated receptor model (see the figure below) to test whether the small measured changes in mexiletine affinity were sufficient to produce the differences in state-dependent block.

The complete original paper reference is cited below:

Mexiletine block of disease-associated mutations in S6 segments of the human skeletal muscle Na⁺ channel, Masanori P. Takahashi and Stephen C. Cannon, 2001, The Journal Of Physiology , 537, 701-714. (Full text and PDF versions of the article are available to subscribers on the JP website.) PubMed ID: 11744749

In this modulated receptor model, R is the fraction of closed resting channels, I is the fast-inactivated fraction, I-Mex represents the fraction of fast-inactivated mexiletine-bound channels and R-Mex is the fraction of drug-bound resting channels.

• takahashi_cannon_2001_version01.cellml