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HCN3 ion channels - roles in sensory neuronal excitability and pain: HCN3 ion channels and pain

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)4661-4675
Number of pages15
JournalThe Journal of Physiology
Issue number17
Early online date9 Jul 2019
Publication statusPublished - 1 Sep 2019


King's Authors


HCN ion channels govern the firing rate of action potentials in the pacemaker region of the heart and in pain‐sensitive (nociceptive) nerve fibres. Intracellular cAMP promotes activation of the HCN4 and HCN2 isoforms, while HCN1 and HCN3 are relatively insensitive to cAMP. HCN2 modulates action potential firing rate in nociceptive neurons and plays a critical role in all modes of inflammatory and neuropathic pain, but the role of HCN3 in nociceptive excitability and pain is less studied. Using antibody staining, we found that HCN3 is expressed in all classes of somatosensory neurons. In small nociceptive neurons, genetic deletion of HCN2 abolished the voltage shift of the Ih current carried by HCN isoforms following cAMP elevation, while the voltage shift was retained following deletion of HCN3, consistent with the sensitivity of HCN2 but not HCN3 to cAMP. Deletion of HCN3 had little effect on the evoked firing frequency in small neurons, but enhanced the firing of medium‐sized neurons, showing that HCN3 makes a significant contribution to the input resistance only in medium‐sized neurons. Genetic deletion of HCN3 had no effect on acute thresholds to heat or mechanical stimuli in vivo, and did not affect inflammatory pain measured with the formalin test. Nerve‐injured HCN3 KO mice exhibited similar levels of mechanical allodynia and thermal hyperalgesia to WT mice, but reduced mechanical hyperalgesia in response to a pinprick. These results show that HCN3 makes some contribution to excitability, particularly in medium‐sized neurons, but has no major influence on acute or neuropathic pain processing.

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