Does nitric oxide modulate transmitter release at the mammalian neuromuscular junction?
1. Application of the nitric oxide (NO) donor, sodium nitrite and the NO synthase substrate l-arginine had no effect on nerve-evoked transmitter release in the rat isolated phrenic nerve/hemidiaphragm preparation; however, when adenosine A(1) receptors were blocked with the adenosine A(1) receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) prior to application of sodium nitrate or l-arginine, a significant increase in transmitter release was observed. In addition, the NO donor s-nitroso-N-acetylpenicillamine (SNAP) significantly increased transmitter release in the presence of DPCPX. In the present study, we have made the assumption that these NO donors elevate the level of NO in the tissue. Future studies should test other NO-donating compounds and also monitor the NO concentrations in the tissue to ensure that these effects are, in fact, NO induced. 2. Elevation of cGMP in this preparation with the guanylyl cyclase activator 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) significantly enhanced transmitter release. In the presence of DPCPX and the selective guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which blocks the production of cGMP, the excitatory effects of sodium nitrite and l-arginine were abolished. 3. These results suggest that NO serves to enhance transmitter release at the rat neuromuscular junction (NMJ) via a cGMP pathway and this facilitation of transmitter release can be blocked with adenosine. Previously, we demonstrated that adenosine inhibits N-type calcium channels. Because NO only affects transmitter release when adenosine A(1) receptors are blocked, we suggest that NO enhances transmitter release by enhancing calcium influx via N-type calcium channels. Further studies are needed to confirm that NO alters transmitter release via cGMP and that this action involves the N-type calcium channel. 4. The results of the present study are consistent with a model of NO neuromodulation that has been proposed for the mammalian vagal-atrial junction. This model suggests that NO acts on NO-sensitive guanylyl cyclase to increase the intracellular levels of cGMP. In turn, cGMP inhibits phosphodiesterase-3, increasing levels of cAMP, which then acts on the N-type calcium channels to enhance calcium influx, leading to an increase in transmitter release. Our only modification to this model for the NMJ is that adenosine serves to block the modulation of transmitter release by NO.
Nickels
Travis J
TJ
Center for Neuroscience, Department of Zoology, Miami University, Oxford, OH 45056, USA.
Reed
Grant W
GW
Drummond
Justin T
JT
Blevins
Dustin E
DE
Lutz
Megan C
MC
Wilson
David F
DF
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D003964:Diaphragm / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D004357:Drug Synergism; D004558:Electric Stimulation / Q000379:methods; D020536:Enzyme Activators / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D009045:Motor Endplate / Q000187:drug effects / Q000502:physiology; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D010791:Phrenic Nerve / Q000502:physiology; D058915:Purinergic P1 Receptor Antagonists; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine / Q000378:metabolism / Q000494:pharmacology; D012977:Sodium Nitrite / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D020536:Enzyme Activators; D007191:Indazoles; D018377:Neurotransmitter Agents; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D058915:Purinergic P1 Receptor Antagonists; D011810:Quinoxalines; D014970:Xanthines; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D001120:Arginine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D012977:Sodium Nitrite