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 carboxy-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. The genes encoding human HCN1 and HCN2 map to chromosomes 5 and 19p13.3, respectively. The genes encoding HCN3 and HCN4 map to chromosomes 1q21.3 and 15q24-q25, respectively.