A family of hyperpolarization-activated mammalian cation channels

Pacemaker activity of spontaneously active neurons1,2,3 and heart cells4,5,6 is controlled by a depolarizing, mixed Na+/K+ current, named Ih (or If in the sinoatrial node of the heart)1,4. This current is activated on hyperpolarization of the plasma membrane. In addition to depolarizing pacemaker cells, Ih is involved in determining the resting membrane potential of neurons1,2 and provides a mechanism to limit hyperpolarizing currents in these cells7,8,9. Hormones and neurotransmitters that induce a rise in cyclic AMP levels increase Ih by a mechanism that is independent of protein phosphorylation, and which involves direct binding of the cyclic nucleotide to the channel that mediates Ih10,11,12,13. Here we report the molecular cloning and functional expression of the gene encoding a hyperpolarization-activated cation channel (HAC1) that is present in brain and heart. This channel exhibits the general properties of Ih channels. We have also identified full-length sequences of two related channels, HAC2 and HAC3, that are specifically expressed in the brain, indicating the existence of a family of hyperpolarization-activated cation channels.