ABSTRACT
Hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels are unusual voltage-gated channels. In contrast to most voltage-gated channels, HCN channels are activated by hyperpolarization, rather than depolarization, of the plasma membrane. In addition, the voltage-dependent activation of HCN channels is allosterically regulated by cyclic nucleotides, which bind directly to the channels. Moreover, HCN channels conduct both Na+ and K+, resulting in a net reversal potential of about –30 mV in physiological solutions. These unusual properties of HCN channels make them important determinants of excitability in many types of cells throughout the body, including cardiac pacemaker cells and central and peripheral neurons. The unique functions and tissue distribution of the four mammalian HCN channel isoforms also make them alluring drug targets for treatment of conditions ranging from heart failure and epilepsy to neuropathic pain and depression.
