Gareth R. Tibbs

The molecular basis of the hyperpolarization‐activated cation channels that underlie the anomalous rectifying current variously termed I_h, I_q, or I_f is discussed. On the basis of the expression patterns and biophysical properties of the newly cloned HCN ion channels, an initial attempt at defining the identity and subunit composition of channels underlying native I_h is undertaken. By comparing the sequences of HCN channels to other members of the K channel superfamily, we discuss how channel opening may be coupled to membrane hyperpolarization and to direct binding of cyclic nucleotide. Finally, we consider some of the questions in cardiovascular physiology and neurobiology that can be addressed as a result of the demonstration that I_h is encoded by the HCN gene family.

Despite recent advances in the identification of ligand-binding and voltage-sensing regions of ion channels, the domains that couple such regions to channel opening have not been identified. Moreover, it is uncertain whether ligand binding or depolarization are obligatory steps that must precede channel opening (according to linear reaction schemes) or whether they act to stabilize the channel in an open state that can exist independently of ligand binding or depolarization (according to cyclic allosteric models). By comparing ligand-independent and ligand-dependent channel openings, we now show that retinal and olfactory cyclic-nucleotide-gated channels are activated by a cyclic allosteric mechanism. We further show that an amino-terminal domain, distinct from the pore and ligand-binding motifs, participates in the allosteric gating transition, accounting for differences in the free energy of gating of the two channels. The allosteric transition provides an important mechanism for tuning the physiological response of ligand-binding proteins, such as cyclic-nucleotide-gated channels, to different biological signals.