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HCN3 ion channels: roles in sensory neuronal excitability and pain.
J Physiol. 2019 09; 597(17):4661-4675.JP

Abstract

KEY POINTS

HCN ion channels conducting the Ih current control the frequency of firing in peripheral sensory neurons signalling pain. Previous studies have demonstrated a major role for the HCN2 subunit in chronic pain but the potential involvement of HCN3 in pain has not been investigated. HCN3 was found to be widely expressed in all classes of sensory neurons (small, medium, large) where it contributes to Ih . HCN3 deletion increased the firing rate of medium but not small, sensory neurons. Pain sensitivity both acutely and following neuropathic injury was largely unaffected by HCN3 deletion, with the exception of a small decrease of mechanical hyperalgesia in response to a pinprick. We conclude that HCN3 plays little role in either acute or chronic pain sensation.

ABSTRACT

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, whereas 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, although 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, whereas 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 knockout mice exhibited similar levels of mechanical allodynia and thermal hyperalgesia to wild-type 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, although it has no major influence on acute or neuropathic pain processing.

Authors+Show Affiliations

Wolfson Centre for Age-Related Research, King's College London, Guy's Campus, London, UK.Wolfson Centre for Age-Related Research, King's College London, Guy's Campus, London, UK.Center for Integrated Protein Science (CIPS-M) and Center for Drug Research, Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany.Wolfson Centre for Age-Related Research, King's College London, Guy's Campus, London, UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31290157

Citation

Lainez, Sergio, et al. "HCN3 Ion Channels: Roles in Sensory Neuronal Excitability and Pain." The Journal of Physiology, vol. 597, no. 17, 2019, pp. 4661-4675.
Lainez S, Tsantoulas C, Biel M, et al. HCN3 ion channels: roles in sensory neuronal excitability and pain. J Physiol. 2019;597(17):4661-4675.
Lainez, S., Tsantoulas, C., Biel, M., & McNaughton, P. A. (2019). HCN3 ion channels: roles in sensory neuronal excitability and pain. The Journal of Physiology, 597(17), 4661-4675. https://doi.org/10.1113/JP278211
Lainez S, et al. HCN3 Ion Channels: Roles in Sensory Neuronal Excitability and Pain. J Physiol. 2019;597(17):4661-4675. PubMed PMID: 31290157.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - HCN3 ion channels: roles in sensory neuronal excitability and pain. AU - Lainez,Sergio, AU - Tsantoulas,Christoforos, AU - Biel,Martin, AU - McNaughton,Peter A, Y1 - 2019/07/27/ PY - 2019/05/08/received PY - 2019/07/08/accepted PY - 2019/7/11/pubmed PY - 2020/8/21/medline PY - 2019/7/11/entrez KW - HCN3 KW - Ion channel KW - Neuron KW - Nociception KW - Pain KW - Sensory SP - 4661 EP - 4675 JF - The Journal of physiology JO - J Physiol VL - 597 IS - 17 N2 - KEY POINTS: HCN ion channels conducting the Ih current control the frequency of firing in peripheral sensory neurons signalling pain. Previous studies have demonstrated a major role for the HCN2 subunit in chronic pain but the potential involvement of HCN3 in pain has not been investigated. HCN3 was found to be widely expressed in all classes of sensory neurons (small, medium, large) where it contributes to Ih . HCN3 deletion increased the firing rate of medium but not small, sensory neurons. Pain sensitivity both acutely and following neuropathic injury was largely unaffected by HCN3 deletion, with the exception of a small decrease of mechanical hyperalgesia in response to a pinprick. We conclude that HCN3 plays little role in either acute or chronic pain sensation. ABSTRACT: 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, whereas 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, although 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, whereas 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 knockout mice exhibited similar levels of mechanical allodynia and thermal hyperalgesia to wild-type 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, although it has no major influence on acute or neuropathic pain processing. SN - 1469-7793 UR - https://www.unboundmedicine.com/medline/citation/31290157/HCN3_ion_channels:_roles_in_sensory_neuronal_excitability_and_pain_ L2 - https://doi.org/10.1113/JP278211 DB - PRIME DP - Unbound Medicine ER -