Description:

Baron Chanda, Ph.D.
Professor of Neuroscience and Biomolecular Chemistry
University of Wisconsin-Madison

Abstract: Despite sharing a common architecture with archetypal voltage-gated ion channels (VGIC), the HCN channels open upon hyperpolarization rather than depolarization. To probe the molecular mechanisms of hyperpolarization gating, we created chimeric channels by swapping portable elements between the depolarization activated EAG channels and the HCN channels derived from mouse. Our studies delineated the junction points for these portable structural modules and reveal interesting properties of these modules. Our studies show that the voltage-sensing domain of HCN channels has the intrinsic ability to drive the channel opening in both hyperpolarizing and depolarizing directions. We have identified key residues that bias this ability of the voltage-sensor to activate channels in one direction or the other. Finally, these studies also reveal the role of gating interface and three residues in the HCN channel pore in preventing reopening upon depolarization.