The Role of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in the Pathophysiology of Absence Epilepsy

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels participate in pacemaker currents, modulating the funny current (I[f ]) in cardiac cells and the hyperpolarization-activated current (I[h]) in neurons. Depending on the neuronal and synaptic localization, HCN channels regulate synaptic integration, long-term potentiation, synaptic transmission, and resting membrane potential. In summary, it contributes to the electrical activity between the excitatory and inhibitory stimuli through its shunting effect. Several second messengers modulate I(h) currents in the synapses by changing voltage-dependent activation kinetics. I(h) currents are being investigated in numerous central nervous system disorders, including epilepsy. On one hand, it is well known that I(h) currents lead to synchronized oscillations in the rhythmic burst mode in thalamocortical neurons underlying the pathophysiology of absence epilepsy. However, much of the evidence is contradictory. Therefore, it is important to understand the dynamic relationship of HCN channels within the oscillatory networks to determine the regional "queerness" of I(h), and we need further investigation to determine if upregulation or downregulation of I(h) is needed in order to suppress seizure activity.

Alpha2-Adrenergic Receptors as a Pharmacological Target for Spike-Wave Epilepsy

“…HCN4 has the slowest kinetics and is strongly modulated by cAMP [ 111 , 112 ]. Melis Yavuz and Filiz Onat in 2018 published a comprehensive review about the role of HCN channels in the pathophysiology of absence epilepsy (also in rat models), where they emphasized the involvement of the second messenger system in modulating HCN channels [ 113 ].…”