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DSS-INDUCED COLITIS REDUCES Ca2+ CURRENTS IN SYMPATHETIC NEURONS OF SUPERIOR MESENTERIC GANGLIA
M Motagally, S Neshat, AE Lomax
Gastrointestinal Diseases Research Group, Queen’s University, Kingston, Ontario
The Superior Mesenteric Ganglia (SMG) is a sympathetic ganglion that regulates gastrointestinal functions such as motility and blood flow. Previous studies have reported that colitis reduces the release of noradrenaline, a sympathetic transmitter. We hypothesized that this reduction in neurotransmitter release is due to inhibition of voltage- gated Ca2+ current (VGCC), as Ca2+ entry into neurons is a critical regulator of neurotransmitter release. Therefore, we compared VGCC amplitude in neurons from normal mice and mice with DSS colitis.
Colitis was induced in male CD1 mice by the administration of 5% dextran sodium sulfate (DSS) in drinking water for five days, followed by three days of normal water. Mice were sacrificed whereupon the SMG was dissected, dissociated, and cultured overnight. Using the perforated patch voltage clamp technique VGCC were measured using a series of command potentials from –60 to 35 mV for 100 ms in 5 mV increments (10 s intervals) from a holding potential of –100 mV. VGCC subtype-specific antagonists (300nM omega-Conotoxin GVIA, N-type; 10µM Nifedipine, L-type; 300 µM omega-Conotoxin MVIIC, N and P/Q type) were used to determine which subtypes contributed to VGCC in these neurons.
DSS-induced colitis caused a significant decrease in VGCC of SMG neurons compared to the control group. The maximal current was decreased approximately 50% compared to the control group (p<0.05 between –25 and +15 mV; DSS n=20, untreated n=23). The reduction in VGCC was specific to the N-type channel subtype (control N-type current= 30.9 pA/pF; DSS N-type current= 4.8 pA/pF; P<0.01), while the L-type channel was unaffected by colitis.
This is the first account of colitis causing a change in VGCC in neurons that innervate the gut. Since N-type VGCC are the primary regulators of neurotransmitter release at sympathetic nerve terminals in the gut, the reduction in VGCC through N-type Ca2+ channels during colitis likely contributes to altered neurotransmitter release and thus may underlie the symptoms associated with colitis.