HCN1 is a primary HCN Pacemaker Channel in Neurons

Rhythmic activity of specialized pacemaker neurons in the brain is necessary to control alertness and circadian timing. Four HCN channels have been identified to generate the pacemaker current I_h or I_q, differing in activation speed, voltage dependence, single-channel conductance, and cAMP sensitivity. Here we show the time-resolved operation of single HCN1, HCN2 and HCN4 channels during the pacemaker depolarization using a dynamic neuronal action potential clamp at femtosiemens resolution. All channels produce a relevant open probability during pacemaker depolarization. However, only mHCN1 channels are significantly activated and deactivated in action potential cycles whereas the gating in mHCN2 and mHCN4 channels is at best barely resolvable and too slow. Simulations suggest that the role of HCN1 channels is to trigger the initial neuronal pacemaker depolarization before other depolarizing conductances take over this role. In conclusion, mHCN1 channels are the primary HCN pacemaker channels that operate as trigger channels for pacemaking.