Membrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neurons
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, de...
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54053-z |
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| author | Lucas J. Handlin Natalie L. Macchi Nicolas L. A. Dumaire Lyuba Salih Erin N. Lessie Kyle S. McCommis Aubin Moutal Gucan Dai |
| author_facet | Lucas J. Handlin Natalie L. Macchi Nicolas L. A. Dumaire Lyuba Salih Erin N. Lessie Kyle S. McCommis Aubin Moutal Gucan Dai |
| author_sort | Lucas J. Handlin |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-fad39d75223c4dd28e6df44fc3615e59 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-fad39d75223c4dd28e6df44fc3615e592024-11-17T12:36:23ZengNature PortfolioNature Communications2041-17232024-11-0115112010.1038/s41467-024-54053-zMembrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neuronsLucas J. Handlin0Natalie L. Macchi1Nicolas L. A. Dumaire2Lyuba Salih3Erin N. Lessie4Kyle S. McCommis5Aubin Moutal6Gucan Dai7Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of MedicineEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of MedicineDepartment of Pharmacology and Physiology, Saint Louis University School of MedicineDepartment of Pharmacology and Physiology, Saint Louis University School of MedicineEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of MedicineEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of MedicineDepartment of Pharmacology and Physiology, Saint Louis University School of MedicineEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of MedicineAbstract 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.https://doi.org/10.1038/s41467-024-54053-z |
| spellingShingle | Lucas J. Handlin Natalie L. Macchi Nicolas L. A. Dumaire Lyuba Salih Erin N. Lessie Kyle S. McCommis Aubin Moutal Gucan Dai Membrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neurons Nature Communications |
| title | Membrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neurons |
| title_full | Membrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neurons |
| title_fullStr | Membrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neurons |
| title_full_unstemmed | Membrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neurons |
| title_short | Membrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neurons |
| title_sort | membrane lipid nanodomains modulate hcn pacemaker channels in nociceptor drg neurons |
| url | https://doi.org/10.1038/s41467-024-54053-z |
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