| 研究実績の概要 |
The patch clamp experiments were focused on several TRPM4 mutations associated with cardiac conduction disorders, e.g., E7K and Q854R mutant. The functional interaction between Nav1.5 and TRPM4 channel was characterized by cable simulation. The results are summarized as follows: 1) By the Iono-C/A recording technique, the gain of function TRPM4 mutations more readily open at more negative membrane potentials and at lower [Ca2+]i condition. It is induced by enhancing the voltage and Ca2+ dependencies of the rate constants of opening (α) and decreasing those of closing (β). These mutations accelerate the closed-to-open state (C-O) transition, meanwhile decelerate the reverse (O-C) transition. 2）1D-cable simulation models incorporating TRPM4 channel and its mutant gating were constructed. The preferred opening by the gain of function mutants tends to cause conduction block. In addition, the decreases in dV/dtmax and CV are consistent with the depolarizing shifts of the resting membrane potential (RMP). The level of RMP plays an important role to determine Nav availability. In this context, the extent of the observed RMP shift reasonably accounts for the decrease in Nav availability, especially at AP upstroke which is estimated from its voltage-dependent inactivation curve. Therefore these results reveal that excessive TRPM4 activities at resting conditions would facilitate Nav inactivation during diastole, thereby slowing the subsequent generation and propagation of the AP.
During this year, the results was published in International Journal of Molecular Sciences.
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| 次年度使用額が生じた理由 |
Research costs will be spent on animal feeding as well as consumables for cell culture, molecular biological, biochemical and electrophysiological experiments. To present the outcome of our study, we are going to join several conferences and submit our study results to certain academic journals.
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