Inhibition of sympathetic N-type voltage-gated Ca2+ current underlies the reduction in norepinephrine release during colitis.
Inflammatory bowel diseases (IBD) are associated with altered neuronal regulation of the gastrointestinal (GI) tract and impairment of norepinephrine release from sympathetic varicosities. The sympathetic innervation of the GI tract modulates motility, blood flow, and secretion, and therefore defective norepinephrine release may contribute to symptom generation in IBD. Accordingly, our aim here was to utilize the mouse model of dextran sulfate sodium (DSS; 5% wt/vol) of IBD to determine how norepinephrine release is reduced during GI inflammation. We hypothesized that the inflammation-induced reduction in norepinephrine release was due to inhibition of voltage-gated Ca(2+) current (I(Ca)) in prevertebral sympathetic neurons. We compared [(3)H]norepinephrine release in the colon and jejunum and I(Ca) amplitude in superior mesenteric ganglion (SMG) neurons from control mice and mice with DSS-induced colitis. Changes to voltage-gated Ca(2+) channels were investigated by fura 2-AM Ca(2+) imaging, perforated patch-clamp electrophysiology, and real-time PCR. Depolarization-induced norepinephrine release from the inflamed colon and uninflamed jejunum was significantly impaired in mice treated with DSS, as was depolarization-induced Ca(2+) influx in SMG neurons. Colitis reduced I(Ca) in SMG neurons by inhibiting omega-conotoxin GVIA (300 nM)-sensitive N-type Ca(2+) channels. The omega-conotoxin GVIA-sensitive component of norepinephrine release was significantly smaller in the colon during colitis. The inhibition of I(Ca) was accompanied by a decrease in mRNA encoding the Ca(2+) channel alpha subunit (CaV 2.2) and a rightward shift in the voltage dependence of activation of I(Ca). These findings suggest that DSS-induced colitis attenuates norepinephrine release in the colon and jejunum due to inhibition of N-type voltage-gated Ca(2+) channels. This may contribute to functional alterations in both inflamed and uninflamed regions of the GI tract during inflammation.
Motagally
Mohamed A
MA
Department of Physiology, Gastrointestinal Diseases Research Unit and Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.
Neshat
Shadia
S
Lomax
Alan E
AE
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D003106:Colon / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D015536:Down-Regulation; D005728:Ganglia, Sympathetic / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D007583:Jejunum / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
C500963:Cacna1b protein, mouse; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D012333:RNA, Messenger; D016264:Dextran Sulfate; D020866:omega-Conotoxin GVIA; D009638:Norepinephrine