The Hyperpolarization-Activated Cyclic Nucleotide–Gated Channels: from Biophysics to Pharmacology of a Unique Family of Ion Channels

Abstract

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels are important members of the voltage-gated pore loop channels family. They show unique features: they open at hyperpolarizing potential, carry a mixed Na/K current, and are regulated by cyclic nucleotides. Four different isoforms have been cloned (HCN1-4) that can assemble to form homo- or heterotetramers, characterized by different biophysical properties. These proteins are widely distributed throughout the body and involved in different physiologic processes, the most important being the generation of spontaneous electrical activity in the heart and the regulation of synaptic transmission in the brain. Their role in heart rate, neuronal pacemaking, dendritic integration, learning and memory, and visual and pain perceptions has been extensively studied; these channels have been found also in some peripheral tissues, where their functions still need to be fully elucidated. Genetic defects and altered expression of HCN channels are linked to several pathologies, which makes these proteins attractive targets for translational research; at the moment only one drug (ivabradine), which specifically blocks the hyperpolarization-activated current, is clinically available. This review discusses current knowledge about HCN channels, starting from their biophysical properties, origin, and developmental features, to (patho)physiologic role in different tissues and pharmacological modulation, ending with their present and future relevance as drug targets.

Selective HCN1 block as a strategy to control oxaliplatin-induced neuropathy

“…Although strongly suggesting a prominent role for HCN channels in OXAinduced neuropathy, these studies lack to demonstrate the nature of the alterations undergone by HCN channels following chronic exposure to platinum compounds, i.e., whether a change in the expression pattern of HCN isoforms takes place, or, rather, their biophysical properties are affected. In a translation perspective, the anti-hyperalgesic potential of "pan" HCN blockers (i.e., not discriminating among HCN isoforms) cannot be fully exploited due to the detrimental effect that block of HCN4 in the sinus atrial node may have on cardiac rhythm (Novella Romanelli et al, 2016;Sartiani et al, 2017;Stillitano et al, 2013) In this work, we demonstrate that nociceptor neurons from OXA-treated rats show significant Ih gain of function in ex vivo recordings. Biochemically, we observed downregulation of HCN2 protein and upregulation of the HCN channels ancillary b-subunit Mink Related Peptide1 (MiRP1), known to increase the open probability of HCN1.…”

Etiology and Pharmacology of Neuropathic Pain

“…A blocker of HCN channels, ivabradine, which is also used clinically to treat angina and heart failure, has been shown to be effective in treating signs of neuropathic pain in animal models through peripheral action on small sensory neurons and to decrease firing frequency in cultured DRG neurons from nerve-injured animals (Noh et al, 2014;Young et al, 2014). More recent work has focused on the search for selective HCN2 blockers (Sartiani et al, 2017) that may abrogate hyperexcitability of DRG neurons without affecting the HCN1 channels that are responsible for controlling cardiac rhythmicity .…”

Neuronal hyperexcitability is a DLK-dependent trigger of HSV-1 reactivation that can be induced by IL-1

“…Increased levels of cAMP can act on nucleotide gated ion channels, including the hyperpolarization activated cyclic nucleotide gated (HCN) channels. HCN channels are K + and Na + channels that are activated by membrane hyperpolarization 55,56 . In the presence of high levels of cAMP, the gating potential of HCN channels is shifted in the positive direction, such that HCN channels can open at resting membrane potential, resulting in an increased propensity of neurons to undergo repeated firing 56-58 .…”