Hyperpolarization-activated Cyclic Nucleotide-gated ion channel 2 (HCN2)

Hyperpolarization-activated Cyclic Nucleotide-gated ion channel 2 (HCN2) is a voltage-gated cation channel that mediates the hyperpolarization-activated current, often referred to as the 'funny' current (If) in the heart or the h-current (Ih) in the brain [6, 9, 11]. Unlike most voltage-gated channels, HCN2 opens upon membrane hyperpolarization and is further modulated by the binding of cyclic nucleotides, such as cAMP, which shifts its activation threshold to more depolarized potentials [6, 13]. It is highly expressed in the thalamus, cortex, and peripheral sensory neurons, where it plays a fundamental role in maintaining the resting membrane potential and regulating rhythmic neuronal firing [3, 15]. In pathological contexts, HCN2 has been identified as a critical 'pacemaker for pain,' particularly in neuropathic and inflammatory states where its sensitization by cAMP leads to spontaneous firing in nociceptive fibers [5, 13]. Furthermore, genetic variants in the HCN2 gene are linked to several forms of epilepsy and severe neurodevelopmental disorders, including febrile seizures and developmental encephalopathy [16, 17]. This makes HCN2 a significant therapeutic target for the development of selective analgesics and anticonvulsants that aim to stabilize neuronal excitability by modulating the channel's gating properties [13, 20].

Other names

BCNG-2BCNG2HAC-1Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2Hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2EIG17FEB2GEFSP11

HCN channel blocker, HCN channel inhibitor, HCN channel partial agonist