Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Currents in Neurons

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are voltage-gated ion channels that activate at potentials more negative than −50 mV and are predominantly permeable to Na⁺ and K⁺ ions. Four HCN subunits (HCN1–4) have been cloned. These subunits have distinct expression patterns and biophysical properties. In addition, cyclic nucleotides as well as multiple intracellular substances including various kinases and phosphatases modulate the expression and function of the subunits. Hence, the characteristics of the current, I_h, are likely to vary among neuronal subtypes. In many neuronal subtypes, I_h is present postsynaptically, where it plays a critical role in setting the resting membrane potential and the membrane resistance. By influencing these intrinsic properties, I_h will affect synaptic potential shapes and summation and thereby affect neuronal excitability. Additionally, I_h can have an effect on resonance properties and intrinsic neuronal oscillations. In some neurons, I_h may also be present presynaptically in axons and synaptic terminals, where it modulates neuronal transmitter release. Hence the effects of I_h on neuronal excitability are complex. It is, however, necessary to fully understand these as I_h has a significant impact on physiological conditions such as learning as well as pathophysiological states such as epilepsy.