Glucocorticoids regulate glutamate and GABA synapse-specific retrograde transmission via divergent nongenomic signaling pathways.
Glucocorticoids exert an opposing rapid regulation of glutamate and GABA synaptic inputs to hypothalamic magnocellular neurons via the activation of postsynaptic membrane-associated receptors and the release of retrograde messengers. Glucocorticoids suppress synaptic glutamate release via the retrograde release of endocannabinoids and facilitate synaptic GABA release via an unknown retrograde messenger. Here, we show that the glucocorticoid facilitation of GABA inputs is due to the retrograde release of neuronal nitric oxide and that glucocorticoid-induced endocannabinoid synthesis and nitric oxide synthesis are mediated by divergent G-protein signaling mechanisms. While the glucocorticoid-induced, endocannabinoid-mediated suppression of glutamate release is dependent on activation of the G(alpha)s G-protein subunit and cAMP-cAMP-dependent protein kinase activation, the nitric oxide facilitation of GABA release is mediated by G(beta)gamma signaling that leads to activation of neuronal nitric oxide synthase. Our findings indicate, therefore, that glucocorticoids exert opposing rapid actions on glutamate and GABA release by activating divergent G-protein signaling pathways that trigger the synthesis of, and glutamate and GABA synapse-specific retrograde actions of, endocannabinoids and nitric oxide, respectively. The simultaneous rapid stimulation of nitric oxide and endocannabinoid synthesis by glucocorticoids has important implications for the impact of stress on the brain as well as on neural-immune interactions in the hypothalamus.
Di
Shi
S
Department of Cell and Molecular Biology, Neurobiology Division,, Tulane University, New Orleans, Louisiana 70118, USA.
Maxson
Marc M
MM
Franco
Alier
A
Tasker
Jeffrey G
JG
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011714:Pyrans / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077285:Rimonabant; D015398:Signal Transduction / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D013873:Thionucleotides / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C508712:(6aR,10aR)-3-(1-methansulfonylamino-4-hexyn-6-yl)6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo(b,d)pyran; D063385:Cannabinoid Receptor Modulators; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005938:Glucocorticoids; D020030:Nitric Oxide Donors; D010880:Piperidines; D011714:Pyrans; D011720:Pyrazoles; D011810:Quinoxalines; C110881:S-nitro-N-acetylpenicillamine; D013873:Thionucleotides; D006153:Guanosine Diphosphate; D009569:Nitric Oxide; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C056723:FG 9041; C023427:guanosine 5'-O-(2-thiodiphosphate); C056639:2-amino-5-phosphopentanoic acid; D013759:Dronabinol; D003907:Dexamethasone; D001120:Arginine; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D010396:Penicillamine; D014633:Valine; D000077285:Rimonabant