Membrane Lipid Nanodomains Modulate HCN Pacemaker Channels in Nociceptor DRG Neurons

• DOI: 10.1101/2023.09.02.556056
• Publication Date: 2023-09-06T17:26:09Z
• Authors: Lucas J. Handlin; Natalie L. Macchi; Nicolas L.A. Dumaire; Lyuba Salih; Erin N. Lessie; Kyle S. McCommis; Aubin Moutal; Gucan Dai
• Keywords: Nociceptor

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 found the dimension cholesterol-enriched ordered membrane domains (OMD) varies considerably, depending on specific cell types. Particularly, nociceptor dorsal root ganglion (DRG) neurons exhibit large OMDs. Disruption OMDs potentiated action potential firing in DRG facilitated opening native hyperpolarization-activated cyclic nucleotide-gated (HCN) pacemaker channels. This increased neuronal is partially due to an open probability altered gating kinetics HCN The effect channels was likely a direct modulation their voltage sensors by In animal models neuropathic pain, observed reduced OMD size loss channel localization within Additionally, cholesterol supplementation inhibited hyperexcitability pain models. These findings suggest disturbances play critical role regulating neurons, influencing modulation.