The HA modular gating scheme used to describe hyperpolarization-dependent activation. (A) Schematic of the HA model showing each functional domain PD, VSD, and CNBD (Materials and Methods). The equilibrium constants are L, H(V), and K. The coupling factors are C, F, and E. (B) Popen vs. voltage predictions of the HA model for spHCNWT channels. Also shown are predictions when VSD equilibrium constant H(V) is increased, the VSD–PD coupling factor F is decreased, or the PD equilibrium constant L is increased (WT: H0 = 0.024, VH = −9.63 mV, F = 10.1, L = 5.91, α_cAMP = 1, α_cGMP = 0.091, α_NocNMP = 0.0021; Increase H: H0 = 1; decrease F = 1.8; increase L = 100).