Membrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neurons

Lucas J. Handlin, Natalie L. Macchi, Nicolas L. A. Dumaire, Lyuba Salih, Erin N. Lessie, Kyle S. McCommis, Aubin Moutal and Gucan Dai ()
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Lucas J. Handlin: Saint Louis University School of Medicine
Natalie L. Macchi: Saint Louis University School of Medicine
Nicolas L. A. Dumaire: Saint Louis University School of Medicine
Lyuba Salih: Saint Louis University School of Medicine
Erin N. Lessie: Saint Louis University School of Medicine
Kyle S. McCommis: Saint Louis University School of Medicine
Aubin Moutal: Saint Louis University School of Medicine
Gucan Dai: Saint Louis University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Cell membranes consist of heterogeneous lipid nanodomains that influence key cellular processes. Using FRET-based fluorescent assays and fluorescence lifetime imaging microscopy (FLIM), we find that the dimension of cholesterol-enriched ordered membrane domains (OMD) varies considerably, depending on specific cell types. Particularly, nociceptor dorsal root ganglion (DRG) neurons exhibit large OMDs. Disruption of OMDs potentiated action potential firing in nociceptor DRG neurons and facilitated the opening of native hyperpolarization-activated cyclic nucleotide-gated (HCN) pacemaker channels. This increased neuronal firing is partially due to an increased open probability and altered gating kinetics of HCN channels. The gating effect on HCN channels is likely due to a direct modulation of their voltage sensors by OMDs. In animal models of neuropathic pain, we observe reduced OMD size and a loss of HCN channel localization within OMDs. Additionally, cholesterol supplementation inhibited HCN channels and reduced neuronal hyperexcitability in pain models. These findings suggest that disturbances in lipid nanodomains play a critical role in regulating HCN channels within nociceptor DRG neurons, influencing pain modulation.

Date: 2024
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DOI: 10.1038/s41467-024-54053-z

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