Biophysical and pharmacological profiling of multiple voltage-gated sodium channel subtypes on QPatch II

著者: Daniel Sauter, Mette T Christensen, Rasmus B Jacobsen, Göran Mattsson

Voltage-gated sodium channels (VGSC) are in the spotlight of drug development as strong evidence is available linking different subtypes to various disease states. VGSC is responsible for the initiation and propagation of action potentials in excitable cells. During this process, the VGSC transitions from a closed to an open into an inactivated state. Interestingly, inhibitory compounds often exhibit different pharmacological profiles dependent upon the conformational state of the ion channel.

In the present work, the second generation QPatch (QPatch II; Sophion Bioscience) was used in combination with adaptive voltage protocols to investigate state-dependent inhibition of tetrodotoxin (TTX), amitriptyline and tetracaine on 8 different VGSC subtypes (Nav1.1-8). A first step was to determine the half-inactivation potential V½(inactivation) for each individual cell. This value was then used during the next steps as a preconditioning pulse. Such an adaptive protocol allowed to determine IC50 values for both the closed and the inactivated state and reduce heterogeneity of the cells. Both IC50 values and biophysical parameters of the different subtypes align well with literature values.