Hcn2, short for hyperpolarization-activated cyclic nucleotide-gated channel 2, is a crucial ion channel. It plays significant roles in multiple neurophysiological functions, such as learning, sensory functions, and pain regulation [1,2]. Hcn2 channels are also involved in maintaining the resting membrane potential and regulating the excitability of neurons. In the heart, members of the HCN ion channel family are known for their role in the pacemaker potential, and Hcn2 specifically has been emerging as a "pacemaker for pain" in nociceptive neurons [2].

Genetic studies have expanded the understanding of Hcn2-related disorders. Mono and biallelic variants in Hcn2 cause severe neurodevelopmental disorders, including developmental delay/intellectual disability and epilepsy [1]. Deletion of Hcn2 from nociceptive neurons abolishes heat-evoked inflammatory pain and all aspects of neuropathic pain, indicating its key role in pain sensation [2]. Pharmacological block or targeted genetic deletion of Hcn2 also abolishes migraine-like pain in rodent models, highlighting its potential as a target for migraine treatment [3]. In a thalamocortical circuit, up-regulation of Hcn2 channels mediates allodynia in mouse models of chronic pain [4]. Additionally, Hcn2 deficiency in Alzheimer's disease is associated with memory deficits and hyperexcitability of dCA1 pyramidal neurons, and overexpressing Hcn2 can rescue these deficits [5].

In conclusion, Hcn2 is essential for various neurophysiological functions, especially in pain-related processes and neural development. Gene knockout or knockdown studies in animal models have revealed its roles in multiple disease conditions, including neuropathic pain, migraine, chronic pain, and Alzheimer's disease. These findings suggest that Hcn2 could be a potential therapeutic target for these diseases.

References:

1. Houdayer, Clara, Phillips, A Marie, Chabbert, Marie, Ziegler, Alban, Legros, Christian. 2024. Mono and biallelic variants in HCN2 cause severe neurodevelopmental disorders. In medRxiv : the preprint server for health sciences, , . doi:10.1101/2024.03.19.24303984. https://pubmed.ncbi.nlm.nih.gov/38562733/

2. Emery, Edward C, Young, Gareth T, McNaughton, Peter A. 2012. HCN2 ion channels: an emerging role as the pacemakers of pain. In Trends in pharmacological sciences, 33, 456-63. doi:10.1016/j.tips.2012.04.004. https://pubmed.ncbi.nlm.nih.gov/22613784/

3. Tsantoulas, Christoforos, Ng, Aidan, Pinto, Larissa, Andreou, Anna P, McNaughton, Peter A. 2022. HCN2 Ion Channels Drive Pain in Rodent Models of Migraine. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 42, 7513-7529. doi:10.1523/JNEUROSCI.0721-22.2022. https://pubmed.ncbi.nlm.nih.gov/36658457/

4. Yu, Jun-Ma, Hu, Rui, Mao, Yu, Chen, Danyang, Jin, Yan. 2022. Up-regulation of HCN2 channels in a thalamocortical circuit mediates allodynia in mice. In National science review, 10, nwac275. doi:10.1093/nsr/nwac275. https://pubmed.ncbi.nlm.nih.gov/36846300/

5. Zhang, Xiaoqin, Zhang, Yiping, Zhang, Ting, Shen, Haowei, Sun, Binggui. 2025. HCN2 deficiency correlates with memory deficits and hyperexcitability of dCA1 pyramidal neurons in Alzheimer's disease. In Alzheimer's research & therapy, 17, 55. doi:10.1186/s13195-025-01704-y. https://pubmed.ncbi.nlm.nih.gov/40016780/