Unlocking the mechanisms of HCN channel gating with locked-open and locked-closed channels

457 C o m m e n t a r y Ion channels are highly specialized to respond to a wide range of environmental stimuli, including transmem-brane voltage and chemical ligands (Hille, 2001). The response of channels to external cues causes a change in their ion conduction, which, in turn, modifies the behavior of excitable and nonexcitable cells. The hyper-polarization-activated and cyclic nucleotide–modified (HCN) family of ion channels, which are important for spontaneous, pacemaking behavior in the heart and neurons, are regulated by both transmembrane voltage and direct binding of cyclic nucleotides (e. HCN channels are composed of four subunits, each containing six transmembrane domains (6TM). HCN channels are similar in primary structure to other 6TM, including voltage-activated potassium (Kv) channels and cyclic nucleotide–gated (CNG) channels (Kaupp et al., 1989; Warmke and Ganetzky, 1994). Similar to CNG channels, HCN contains a C-terminal cyclic nucleotide–binding domain (Zagotta et al., 2003). The mechanisms underlying the regulation of HCN channels and other 6TM channels are the subject of intensive work. Some common mechanistic themes are shared by 6TM channels: they have a pore region that is selective for particular ions, a gate domain that opens to allow the flow of ions or closes to restrict the flow of ions, and sensory domains that interact with stimuli. The mechanism by which sensory domains are coupled to gates is not well understood. Two studies by the Yel-len laboratory in the September 2012 issue (Kwan et al., 2012) and in this issue (see Ryu and Yellen) of the JGP cast new light on the structural mechanism and ener-getics of coupling of the voltage sensor to the gate in HCN channels. These new findings are particularly notable in that gating in HCN channels differs markedly from that of closely related 6TM channels. A hallmark of the 6TM domain Kv and Ca 2+-activated K (BK) channels is that they are all activated (opened) by depolarizing voltages and closed by hyperpolarizing voltages. In contrast, Correspondence to Matthew C. Trudeau: m t r u d e a u @ s o m. m a r y l a n d. e d u HCN channels are activated (opened) by hyperpolariz-ing voltages and closed by depolarizing voltages. The voltage sensor of HCN and K channels undergoes similar movements What is the mechanism by which HCN channels exhibit the " opposite " voltage dependence of Kv and BK chan-nels? Initially, one potential …