A family of hyperpolarization-activated mammalian cation channels

Pacemaker activity of spontaneously active neurons(1-3) and heart cells(4-6) is controlled by a depolarizing, mixed Na+/K+ current, named I-h (or I-f 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, I-h is involved in determining the resting membrane potential of neurons(1,2) and provides a mechanism to limit hyperpolarizing currents in these cells(7-9). Hormones and neurotransmitters that induce a rise in cyclic AMP levels increase I-h by a mechanism that is independent of protein phosphorylation, and which involves direct binding of the cyclic nucleotide to the channel that mediates I-h(10-13). 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 I-h 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.