The study of multiple ion channel gating models and mechanisms

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Recent advancements in protein structural determination, structural predictions, structural modelling, and bioinformatics have significantly improved our understanding of ion channel gating models and mechanisms. Despite these improvements in technology, the transient and sporadic nature of multiple open and closed states in ion channels remains a challenge to study. These states are observable in electrophysiology studies but might be difficult to capture through structural determination techniques such as cryo-electron microscopy (cryo-EM) or may not appear as stable structures in prediction and modeling approaches. Bioinformatics are instrumental in generating hypotheses for further investigation. By examining functional and sequence differences across species or isoforms, these methods yield profound insights into ion channel gating mechanisms. Nevertheless, these hypotheses must be rigorously tested in functional studies. Hence, although ion channel research has seen huge advancements from these recent technological improvements, there is still no technique that can substitute electrophysiology experiments in the degree of functional information provided. To gain a strong understanding of ion channel gating models and mechanisms and the integration of knowledge provided by recent improved technological advances of, I chose to study thermoTRP channels, six-transmembrane voltage-gated or ligand-gated ion channels, as well as BK channels, the voltage- and calcium-gated potassium channels. Particularly, I have developed a theory for temperature-dependent gating in thermoTRP channels, generated hypotheses for voltage-gating mechanisms in six-transmembrane voltage-gated channels from sequence-based bioinformatics integrated with structural knowledge, and investigated BK’s voltage-gating mechanism by performing single-channel electrophysiology studies of BK based on hypotheses generated from the bioinformatics approach.



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