Signalling pathway of nitric oxide in synaptic GABA release in the rat paraventricular nucleus.
In the paraventricular nucleus (PVN) of the hypothalamus, nitric oxide (NO) inhibits sympathetic outflow through increased GABA release. However, the signal transduction pathways involved in its action remain unclear. In the present study, we determined the role of cGMP, soluble guanylyl cyclase, and protein kinase G in the potentiating effect of NO on synaptic GABA release to spinally projecting PVN neurones. The PVN neurones were retrogradely labelled by a fluorescent tracer injected into the thoracic spinal cord of rats. Whole-cell voltage-clamp recordings were performed on labelled PVN neurones in the hypothalamic slice. Bath application of the NO donor, S-nitroso-N-acetyl-penicillamine (SNAP), reproducibly increased the frequency of miniature GABAergic inhibitory postsynaptic currents (mIPSCs) without changing the amplitude and the decay time constant. Neither replacement of Ca2+ with Co2+ nor application of Cd2+ to block the Ca2+ channel altered the effect of SNAP on mIPSCs. Also, the effect of SNAP on mIPSCs was not significantly affected by thapsigargin, a Ca2+-ATPase inhibitor that depletes intracellular Ca2+ stores. Application of a membrane-permeant cGMP analogue, pCPT-cGMP, mimicked the effect of SNAP on mIPSCs in the presence of a phosphodiesterase inhibitor, IBMX. Furthermore, both the soluble guanylyl cyclase inhibitor, ODQ, and the specific protein kinase G inhibitor, Rp pCPT cGMP, abolished the effect of SNAP on mIPSCs. Thus, these data provide substantial new information that NO potentiates GABAergic synaptic inputs to spinally projecting PVN neurones through a cGMP-protein kinase G pathway.
Li
De-Pei
DP
Department of Anaesthesiology, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
Chen
Shao-Rui
SR
Finnegan
Thomas F
TF
Pan
Hui-Lin
HL
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D006152:Cyclic GMP / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D006162:Guanylate Cyclase; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000071756:Soluble Guanylyl Cyclase; D013569:Synapses / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D015220:Calcium Channels; D020030:Nitric Oxide Donors; D018160:Receptors, Cytoplasmic and Nuclear; C110881:S-nitro-N-acetylpenicillamine; D009569:Nitric Oxide; D005680:gamma-Aminobutyric Acid; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D010396:Penicillamine; D006152:Cyclic GMP; D002118:Calcium