A FAMILY OF HYPERPOLARIZATION-ACTIVATED MAMMALIAN CATION CHANNELS

Pacemaker activity of spontaneously active neurons(1-3) and heart cell s(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 a ctivated on hyperpolarization of the plasma membrane. In addition to d epolarizing pacemaker cells, I-h is involved in determining the restin g membrane potential of neurons(1,2) and provides a mechanism to limit hyperpolarizing currents in these cells(7-9). Hormones and neurotrans mitters that induce a rise in cyclic AMP levels increase I-h by a mech anism that is independent of protein phosphorylation, and which involv es direct binding of the cyclic nucleotide to the channel that mediate s I-h(10-13). Here we report the molecular cloning and functional expr ession of the gene encoding a hyperpolarization-activated cation chann el (HAC1) that is present in brain and heart. This channel exhibits th e general properties of I-h channels. We have also identified full-len gth sequences of two related channels, HAC2 and HAC3, that are specifi cally expressed in the brain, indicating the existence of a family of hyperpolarization-activated cation channels.