| 研究実績の概要 |
According to the atomic structure of TRPM4 channel, the residue "Q854" is located on the S2-S3 intracellular helix, which is exposed to the cytoplasm, but distant from the pre-S1 helix and the TRP domain region. The S2-S3 helix forms a narrow cleft with the TRP domain, and Ca2+ may pass through the cleft into the hypothetical binding pocket. Thus structural changes due to Q854R mutation may greatly alter the size of the cleft, and potentially affect the Ca2+-mediated gating control. Accordingly, Q854R mutation may open more easily and close more slowly. These are consistent with the results of our experiments and simulations.
Furthermore, the heterogeneous conduction disturbances in our 2D simulation displays that in the vicinity of fibroblast-like cells with shallow membrane potentials, prolonged depolarization occurs due to the extended activating effect of the TRPM4 mutations. Consequently, the inactivation of Nav1.5 channels accumulates, leading to a decrease in local currents flowing from the excitation front to adjacent non-excitable areas. As stimulation is repeated, the "source" current (i.e., Na+ current) decreases. The extent of this impairment becomes more pronounced in regions where tissue homogeneity and isotropy are lost, resulting in various patterns of conduction disturbances.
Ex vivo experiments demonstrats that mechanical stimulation of endocardial Purkinje fibers could induce various types of arrhythmias,including conduction block and ventricular tachycardia. The mitigating effect of the TRPM4 blocker underscores the pivotal role of TRPM4 overactivation.
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