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The Dysferlin homolog fer‐1 is required for efficient cholinergic synaptic transmission in C. elegans
Author(s) -
Krajacic Predrag,
Mosqueira Matias,
Hermanowski Jane,
Lozynska Olga,
Shen Xiaoning,
Arratia Paulo,
Khurana Tejvir S.,
Lamitina Todd
Publication year - 2009
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/fasebj.23.1_supplement.lb137
Subject(s) - dysferlin , cholinergic , neuromuscular junction , biology , acetylcholine , microbiology and biotechnology , neuroscience , neurotransmission , muscular dystrophy , endocrinology , genetics , receptor
Limb Girdle Muscular Dystrophy 2B (LGMD2B) is a progressive and incurable muscle disorder. Mutations in the Dysferlin gene cause LGMD2B, but the molecular mechanisms underlying disease pathogenesis are unclear. To better understand the pathogenesis of this disease, we studied the C. elegans Dysferlin homolog fer‐1 . Previous studies have characterized fer‐1 only with regards to its roles in spermatogenesis. We found that fer‐1 is also expressed in muscle, where it regulates the localization of post‐synaptic acetylcholine receptors at the neuromuscular junction, suggesting a new role for Dysferlin as a regulator of cholinergic synaptic transmission. Consistent with these data, fer‐1 mutants were resistant to drugs that increase cholinergic signaling, and electrophysiological approaches confirm that fer‐1 mutants have a defect in acetylcholine‐dependent synaptic signaling. Acute administration of a cholinesterase inhibitor improved the excitability and functional properties of fer‐1 muscle. Given the strong evolutionary conservation in synaptic physiology between C. elegans and humans, these data suggest that disruption of cholinergic signaling may contribute to LGMD2B pathology and that drugs enhancing cholinergic signaling might be an effective therapeutic strategy for treatment. Supported by NIH Training Grant in Muscle Biology (T32 AR‐053461‐02) and ITMAT (UL1RR024134) grant.