Pacemaking and pacemaker current in cardiac and neuronal cells: a multi-method electrophysiological approach for evaluating innovative blockers and modulatory signals

Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are membrane proteins, which mediate a Na+/K+ current (If/Ih), that is activated by hyperpolarization and regulated by intracellular cAMP/cGMP levels. HCN channel family is composed by four isoforms (HCN1-4) that are expressed in the heart and the nervous system, where they are involved in pacemaker activities, excitability and pain perception. Alterations of expression and/or function of these channels are associated to pathological conditions such as heart hypertrophy and failure, neuropathic pain and specific form of epilepsy. For these reasons, HCN channels represent valuable targets to uncover novel pharmacological molecules and endogenous mediators capable to modulate their function or dysfunction in cardiac and neuronal physiology and pathology. Ivabradine is the first and only HCN blocker employed in current clinical use as specific bradycardic agent in patients with stable angina and failure, intolerant or not-responsive to -blockers. Furthermore, the function of distinct HCN isoforms in the central and peripheral nervous system has opened to new applications of HCN blockers. In line with this, a recent clinical study has indicated ivabradine as effective drug for neuropathic pain relief, further confirming the potentials of HCN blockers as innovative drugs for neurological disorders. However, ivabradine is unable to discriminate among the four channel isoforms, thereby lacking tissue specificity, similarly to other HCN antagonists such as zatebradine and cilobradine. During the last decade, the research group I joined during my PhD has identified novel zatebradine derivatives among which MEL57A and MEL55A display higher selectivity toward HCN1/HCN2 isoforms over HCN4 and have been successfully tested in animal models of neuropathic pain; differently, EC18 displays higher selectivity toward HCN4 isoform and has proved effective against specific forms of experimental epilepsy. Despite main physiological signals involved in HCN channel ...