Cartoon model for the energetics of activation by voltage and cAMP in a HCN2 channel. A channel is assumed to adopt only one open (O) and one closed (C) state. According to the Eyring rate theory (Glasstone et al., 1941), the transition between the two states requires an amount of free energy ΔG to reach the activation energy Ea of the transition state TS. The major effect on activation is that of voltage (thick red arrows): At −30 mV, ΔG is much higher in O than in C, whereas at −140 mV, ΔG is moderately higher in C than in O. The binding of cAMP to the four subunits (green circles) is assumed to increase and decrease ΔG in the closed and open state, respectively. In the closed state, the energy contributions for the four binding steps are additive, whereas in the open state, these energy contributions are only additive for the quadruple, triple, and trans-double ligated channel and the cis-double and the single ligated channel do not change ΔG with respect to the empty channel.
