HCN Channels Modulators: The Need for Selectivity

Abstract

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, the molecular correlate of the hyperpolarization-activated current (I f /I h ), are membrane proteins which play an important role in several physiological processes and various pathological conditions. In the Sino Atrial Node (SAN) HCN4 is the target of ivabradine, a bradycardic agent that is, at the moment, the only drug which specifically blocks I f . Nevertheless, several other pharmacological agents have been shown to modulate HCN channels, a property that may contribute to their therapeutic activity and/or to their side effects.HCN channels are considered potential targets for developing drugs to treat several important pathologies, but a major issue in this field is the discovery of isoform-selective compounds, owing to the wide distribution of these proteins into the central and peripheral nervous systems, heart and other peripheral tissues. This survey is focused on the compounds that have been shown, or have been designed, to interact with HCN channels and on their binding sites, with the aim to summarize current knowledge and possibly to unveil useful information to design new potent and selective modulators.

Inhibitory Effective Perturbations of Cilobradine (DK-AH269), A Blocker of HCN Channels, on the Amplitude and Gating of Both Hyperpolarization-Activated Cation and Delayed-Rectifier Potassium Currents

“…It is also necessary to point out that the potential of HCN blockers in cardiac pathologies and in the management of pain is well established and that the compounds able to increase I h (e.g., oxaliplatin) may have the therapeutic potential [42,43]. Caution thus entails being raised in attributing the action of CIL on either cardiac function or neuronal networks widely to the block of I h [2,18,19,30,[34][35][36]44,45]. Moreover, the exposure to CIL has been reported to modulate balance function, given that it might concertedly influence both functional HCN channels (i.e., HCN1) in vestibular hair cells of the inner ear [44] and the K v 3.1 channels, which are enriched in the auditory pathway [46].…”

Muscarinic modulation of M and h currents in gerbil spherical bushy cells

“…The name I h comes from its unusual voltage-dependency. Indeed most of the channels are open when the membrane potential is hyperpolarized but a proportion of HCN channels stay tonically open at resting potential and maintain a resting state close to action potential threshold [20,37]. Four different isoforms of HCN channels exist, HCN1 to HCN4.…”

“…Part of this effect can result from the decrease of adenosine-3',5'-cyclic monophosphate (cAMP) and/or guanosine-3',5'-cyclic monophosphate (cGMP). These cyclic nucleotides regulate HCN channels by shifting the voltage of half-maximal activation (V 1/2 ) to more positive values [20,37]. Thus, reducing the cyclic nucleotide availability shifts the activation curve to a more negative value.…”

“…It can affect the resting membrane potential and influence excitability [17][18][19]. I h is mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels [20]. In vitro data have shown that I h is sensitive to muscarinic activation in striatal cholinergic interneurons [21].…”

Characterization of Effectiveness in Concerted Ih Inhibition and IK(Ca) Stimulation by Pterostilbene (Trans-3,5-dimethoxy-4′-hydroxystilbene), a Stilbenoid

“…Hyperpolarization-activated cation current (I h ) has increasingly been considered to be an important determinant of repetitive electrical activity inherent in heart cells and in a variety of neurons, and neuroendocrine or endocrine cells [32][33][34][35][36][37][38][39]. This current is a mixed inward Na + /K + current, which is sensitive to blocking by different compounds such as CsCl, ivabradine or zatebradine [40,41], and increased amplitude of its own accord can act to depolarize membrane potential to the threshold required for elicitation of action potential (AP) [33,[35][36][37]42]. The current is regarded to be carried by channels of the hyperpolarization-activated cyclic nucleotide-gated (HCN) gene family, which belongs to the superfamily of voltage-gated K + channels and cyclic nucleotide-gated channels [36,43].…”