Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are nonselective ligand-gated cation channels in the plasma membranes of heart and brain cells. HCN channels are sometimes referred to as ?pacemaker channels? because they help to generate rhythmic activity within groups of heart and brain cells. They are highly expressed in spontaneously active cardiac regions, such as the sinoatrial node (SAN, the natural pacemaker region), the atrioventricular node (AVN) and the Purkinje fibres of conduction tissue. HCN channels are encoded by four genes (HCN1, 2, 3, 4) and are widely expressed throughout the heart and the central nervous system. HCN channels are homotetramers of four subunits and conduct a Na+ and K+ current with a permeability of 1:4. The mixed sodium?potassium current activates upon hyperpolarization at voltages in the diastolic range (normally from ?60/?70 mV to ?40 mV). At the end of a sinoatrial action potential, the membrane repolarizes below ?40/?50 mV, the "funny current" is activated and supplies inward current, which is responsible for starting the diastolic depolarization phase (DD); by this mechanism, the funny current controls the rate of spontaneous activity of sinoatrial myocytes, hence the cardiac rate. HCN channels are involved in controlling the rhythmic activity of pacemaker current in autorythymic cells in heart and neuronal processes such as dendritic integration and synaptic transmission.