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NEUROREGULATION AND MOTILITY

Inhibition of sympathetic N-type voltage-gated Ca²⁺ current underlies the reduction in norepinephrine release during colitis

Departments of Physiology and Medicine, Gastrointestinal Diseases Research Unit and Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada

Submitted 8 January 2009 ; accepted in final form 26 February 2009

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 Ca²⁺ current (I_Ca) in prevertebral sympathetic neurons. We compared [³H]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 Ca²⁺ channels were investigated by fura 2-AM Ca²⁺ 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 Ca²⁺ influx in SMG neurons. Colitis reduced I_Ca in SMG neurons by inhibiting -conotoxin GVIA (300 nM)-sensitive N-type Ca²⁺ channels. The -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 Ca²⁺ 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 Ca²⁺ channels. This may contribute to functional alterations in both inflamed and uninflamed regions of the GI tract during inflammation.

sympathetic postganglionic neuron; inflammation; calcium current