Gabapentin modulates HCN4 channel voltage-dependence

Authors

Han Shen Tae, University of MelbourneFollow
Kelly M. Smith, Hunter Medical Research Institute, University of Newcastle
Alison Marie Phillips, University of Melbourne
Kieran Boyle, University of Glasgow
Melody Li, University of Melbourne
Ian Forster, University of Melbourne
Robert Hatch, University of Melbourne
Robert Richardson, University of Melbourne
David I. Hughes, University of Glasgow
Brett Graham, Hunter Medical Research Institute, University of Newcastle
Steven Petrou, University of Melbourne
Christopher Reid, University of Melbourne

RIS ID

116079

Publication Details

Tae, H., Smith, K. M., Phillips, A. Marie., Boyle, K. A., Li, M., Forster, I. C., Hatch, R. J., Richardson, R., Hughes, D. I., Graham, B. A., Petrou, S. & Reid, C. A. (2017). Gabapentin modulates HCN4 channel voltage-dependence. Frontiers in Pharmacology, 8 554-1-554-13.

Additional Publication Information

This Document is protected by copyright and was first published by Frontiers. All rights reserved. It is reproduced with permission

Abstract

Gabapentin (GBP) is widely used to treat epilepsy and neuropathic pain. There is evidence that GBP can act on hyperpolarization-activated cation (HCN) channel-mediated I_h in brain slice experiments. However, evidence showing that GBP directly modulates HCN channels is lacking. The effect of GBP was tested using two-electrode voltage clamp recordings from human HCN1, HCN2, and HCN4 channels expressed in Xenopus oocytes. Whole-cell recordings were also made from mouse spinal cord slices targeting either parvalbumin positive (PV⁺) or calretinin positive (CR⁺) inhibitory neurons. The effect of GBP on I_h was measured in each inhibitory neuron population. HCN4 expression was assessed in the spinal cord using immunohistochemistry. When applied to HCN4 channels, GBP (100 µM) caused a hyperpolarizing shift in the voltage of half activation (V_1/2 ) thereby reducing the currents. Gabapentin had no impact on the V_1/2 of HCN1 or HCN2 channels. There was a robust increase in the time to half activation for HCN4 channels with only a small increase noted for HCN1 channels. Gabapentin also caused a hyperpolarizing shift in the V_1/2 of I_h measured from HCN4-expressing PV⁺ inhibitory neurons in the spinal dorsal horn. Gabapentin had minimal effect on I_h recorded from CR⁺ neurons. Consistent with this, immunohistochemical analysis revealed that the majority of CR⁺ inhibitory neurons do not express somatic HCN4 channels. In conclusion, GBP reduces HCN4 channel-mediated currents through a hyperpolarized shift in the V_1/2 . The HCN channel subtype selectivity of GBP provides a unique tool for investigating HCN4 channel function in the central nervous system. The HCN4 channel is a candidate molecular target for the acute analgesic and anticonvulsant actions of GBP.