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Endoplasmic reticulum stress in the dorsal root ganglia regulates large‐conductance potassium channels and contributes to pain in a model of multiple sclerosis
Author(s) -
Yousuf Muhammad Saad,
Samtleben Samira,
Lamothe Shawn M.,
Friedman Timothy N.,
Catuneanu Ana,
Thorburn Kevin,
Desai Mansi,
Tenorio Gustavo,
Schenk Geert J.,
Ballanyi Klaus,
Kurata Harley T.,
Simmen Thomas,
Kerr Bradley J.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202001163r
Subject(s) - endoplasmic reticulum , unfolded protein response , nociceptor , dorsal root ganglion , experimental autoimmune encephalomyelitis , multiple sclerosis , medicine , neuropathic pain , endocrinology , chemistry , neuroscience , pharmacology , microbiology and biotechnology , immunology , nociception , biology , receptor , dorsum , anatomy
Neuropathic pain is a common symptom of multiple sclerosis (MS) and current treatment options are ineffective. In this study, we investigated whether endoplasmic reticulum (ER) stress in dorsal root ganglia (DRG) contributes to pain hypersensitivity in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Inflammatory cells and increased levels of ER stress markers are evident in post‐mortem DRGs from MS patients. Similarly, we observed ER stress in the DRG of mice with EAE and relieving ER stress with a chemical chaperone, 4‐phenylbutyric acid (4‐PBA), reduced pain hypersensitivity. In vitro, 4‐PBA and the selective PERK inhibitor, AMG44, normalize cytosolic Ca 2+ transients in putative DRG nociceptors. We went on to assess disease‐mediated changes in the functional properties of Ca 2+ ‐sensitive BK‐type K + channels in DRG neurons. We found that the conductance‐voltage (GV) relationship of BK channels was shifted to a more positive voltage, together with a more depolarized resting membrane potential in EAE cells. Our results suggest that ER stress in sensory neurons of MS patients and mice with EAE is a source of pain and that ER stress modulators can effectively counteract this phenotype.