Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Channels in Epilepsy

Abstract

Epilepsy is a common brain disorder characterized by the occurrence of spontaneous seizures. These bursts of synchronous firing arise from abnormalities of neuronal networks. Excitability of individual neurons and neuronal networks is largely governed by ion channels and, indeed, abnormalities of a number of ion channels resulting from mutations or aberrant expression and trafficking underlie several types of epilepsy. Here, we focus on the hyperpolarization-activated cyclic nucleotide-gated ion (HCN) channels that conduct Ih current. This conductance plays complex and diverse roles in the regulation of neuronal and network excitability. We describe the normal function of HCN channels and discuss how aberrant expression, assembly, trafficking, and posttranslational modifications contribute to experimental and human epilepsy.

Figure 1.

Abnormal hyperpolarization-activated cyclic nucleotide-gated ion (HCN) channel regulation and assembly following seizures. HCN channel subunits consist of six transmembrane segments (top left). The cytoplasmic carboxyl terminus contains a 120-amino-acid cyclic nucleotide-binding domain (CNBD). HCN1 messenger RNA (mRNA) and protein levels are significantly reduced in the hippocampus following seizures in many animal models of epilepsy; HCN2 levels do not alter appreciably (top right). Altered HCN channel assembly following seizures may result from a reduction of HCN1 subunits (bottom). SF, Silencer factor; cAMP, cyclic adenosine 3′, 5′-monophosphate.