Abstract
Cyclic nucleotide-binding domain (CNBD) channels are critical components of numerous bioelectrical processes, including cardiac pacemaking, neuronal signaling, phototransduction in the eye, and stomatal regulation in plants. While members of this channel family share a conserved overall structure, they exhibit striking differences in voltage sensitivity. Hyperpolarization-activated cyclic nucleotide-gated channels are activated by membrane hyperpolarization, whereas ether-à-go-go channels open upon depolarization. Mutagenesis and chimeragenesis studies have revealed that some mutants display bipolar gating behavior-remaining closed at intermediate membrane potentials but capable of opening in response to both hyperpolarization and depolarization. Remarkably, in certain cases, just a few mutations are sufficient to reverse the intrinsic gating polarity of the channel. This degree of diversity and plasticity in voltage-dependent gating appears to be unique to the CNBD clade and is not adequately explained by existing models. In this study, we systematically evaluate current models and propose a revised framework that better accounts for the full range of voltage-gating behaviors observed in CNBD channels.