Hcn2, short for hyperpolarization-activated cyclic nucleotide-gated channel 2, is a crucial ion channel. It is well-known for its role in the pacemaker potential of the heart and also plays important roles in various neurophysiological functions, including learning, sensory functions, and pain sensation [1]. Hcn2 channels are involved in multiple biological pathways, such as those related to cyclic nucleotide-mediated neuronal excitability. Dysfunction of Hcn2 is associated with various brain disorders, highlighting its overall biological importance. Genetic models, especially gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying Hcn2.

In rodent models, deletion of Hcn2 from nociceptive neurons abolishes heat-evoked inflammatory pain and all aspects of neuropathic pain, indicating its role as a “pacemaker for pain” [1]. In migraine rodent models, pharmacological block or targeted genetic deletion of Hcn2 abolishes migraine-like pain, suggesting Hcn2 as a potential target for migraine treatment [2]. In a mouse model of chronic pain, up-regulation of Hcn2 channels in a thalamocortical circuit mediates allodynia, and down-regulation of Hcn2 in relevant neurons alleviates allodynia [3]. In Alzheimer's disease mouse models, Hcn2 deficiency correlates with memory deficits and hyperexcitability of dCA1 pyramidal neurons, and overexpressing Hcn2 can rescue related functions [4].

In conclusion, Hcn2 is essential for normal physiological functions, especially in pain-related sensations and certain neurophysiological processes. Studies using KO/CKO mouse models have significantly contributed to understanding its role in diseases such as pain-related disorders, migraine, chronic pain, and Alzheimer's disease, providing potential targets for treatment.