PT  - JOURNAL ARTICLE
AU  - Sartiani, Laura
AU  - Mannaioni, Guido
AU  - Masi, Alessio
AU  - Novella Romanelli, Maria
AU  - Cerbai, Elisabetta
ED  - Garland, Christopher J.
TI  - The Hyperpolarization-Activated Cyclic Nucleotide–Gated Channels: from Biophysics to Pharmacology of a Unique Family of Ion Channels
AID  - 10.1124/pr.117.014035
DP  - 2017 Oct 01
TA  - Pharmacological Reviews
PG  - 354--395
VI  - 69
IP  - 4
4099  - http://pharmrev.aspetjournals.org/content/69/4/354.short
4100  - http://pharmrev.aspetjournals.org/content/69/4/354.full
SO  - Pharmacol Rev2017 Oct 01; 69
AB  - 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.