Hyperpolarization-activated, cyclic nucleotide-binding channels (HCN) are voltage-gated cation channels that are activated by direct binding of intracellular cyclic nucleotides. The HCN family consists of four members (HCN1-4), each with a core transmembrane segment domain and a C-terminal 120 amino-acid cyclic nucleotide-binding domain motif. HCN channels are expressed in the brain, heart, thalamus and testis. The pacemaker properties of HCN channels contribute to spontaneous rhythmic activity in the brain and heart. HCN3 contains a segment characterized by a series of positively charged amino acids at every third position. This region designated S4 is likely to be the voltage sensor of the protein. In the brain, HCN3 and HCN4 exhibit subcortical distribution mainly concentrated in the hypothalamus and thalamus, respectively.