Nitric oxide-dependent long-term potentiation is blocked by a specific inhibitor of soluble guanylyl cyclase.
The diffusible second messenger, nitric oxide, is synthesised in central neurons in response to activation of glutamate receptors or other stimuli that increase cytosolic Ca2+ concentrations. Among the many roles suggested for nitric oxide in the central nervous system is that of mediating synaptic plasticity. For example, long-term potentiation in the CA1 region of the rat hippocampus was reported to be blocked by inhibitors of nitric oxide synthase and exogenous nitric oxide has been claimed to induce an enduring enhancement of synaptic strength under certain conditions. These findings, however, are controversial and even when a participation of nitric oxide is evident, the transduction mechanism is unclear. A well-known action of nitric oxide is to stimulate the soluble form of guanylyl cyclase, thereby evoking an accumulation of cyclic GMP in target cells but several other mechanisms have been proposed, including stimulation of ADP ribosyltransferase or cyclooxygenase, and nitrosylation of protein thiol residues. The identification of a selective inhibitor of soluble guanylyl cyclase, the oxadiazoloquinoxaline derivative, ODQ, provides, for the first time, the means to investigate the importance of the cyclic GMP pathway in nitric oxide signal transduction. We find that ODQ and the nitric oxide synthase inhibitor, nitroarginine, reduce hippocampal long-term potentiation in an equal and mutually exclusive manner, suggesting that the actions of nitric oxide in this phenomenon are entirely mediated through cyclic GMP. The experiments also show that there is a component of long-term potentiation that involves neither nitric oxide nor cyclic GMP.
Boulton
C L
CL
Neuroscience Research Group, Wellcome Research Laboratories, Beckenham, Kent, U.K.
Southam
E
E
Garthwaite
J
J
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D006152:Cyclic GMP / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D008046:Lip / Q000187:drug effects*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine; D010069:Oxadiazoles / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D012995:Solubility
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP