A family of hyperpolarization-activated mammalian cation channels

Abstract

Pacemaker activity of spontaneously active neurons^1,2,3 and heart cells^4,5,6 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 neurons¹,² and provides a mechanism to limit hyperpolarizing currents in these cells^7,8,9. 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^10,11,12,13. 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 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.