Seminar Speaker – Dr. Baron Chanda

Hyperpolarization-activated and cyclic nucleotide–gated (HCN) channels generate rhythmic activity in the heart and brain. Despite sharing a common architecture with archetypal voltage-gated ion channels (VGIC), the HCN channels open upon hyperpolarization rather than depolarization. Using structure-guided protein engineering and sequence analysis, we have systematically identified the essential molecular determinants of gating polarity. Our studies reveal that the HCN voltage-sensor is a bipolar switch that has the potential to drive pore opening in both hyperpolarizing and depolarizing directions. Structural elements in the pore and the cytoplasmic C-terminal domains of HCN channel act in concert to prevent pore opening at depolarized potentials under physiological conditions. Our findings reveal an unexpected common principle underpinning voltage gating in the VGIC superfamily.