Mechanism of nitric oxide action on inhibitory GABAergic signaling within the nucleus tractus solitarii.
The cellular mechanisms mediating nitric oxide (NO) modulation of the inhibitory transmission in the nucleus tractus solitarii (NTS) remain unclear, even though this could be extremely important for various physiological and pathological processes. Specifically, in the NTS NO-evoked glutamate and gamma-aminobutyric acid (GABA) release might contribute to pathological hypertension. In cultured rat brainstem slices, NTS GABAergic neurons were targeted using an adenoviral vector to express enhanced green fluorescent protein and studied with a combination of patch clamp and confocal microscopy. Low nanomolar concentrations of NO increased intracellular Ca2+ concentration ([Ca2+]i) in somata, dendrites, and putative axons of GABAergic neurons, with axons being the most sensitive compartment. This effect was cGMP mediated and not related to depolarization or indirect presynaptic effects on glutamatergic transmission. Blockade of the cyclic adenosine diphosphate ribose (cADPR)/ryanodine-sensitive stores but not the inositol triphosphate-sensitive stores, inhibited NO effect. Since cADPR/ryanodine-sensitive stores are implicated in the Ca2+-induced Ca2+ release, NO can be expected to potentiate GABA release. In support of this notion, a cADPR antagonist abolished the NO-induced potentiation of GABAergic inhibitory postsynaptic potentials in the NTS. Thus, the NO-cGMP-cADPR-Ca2+ pathway, previously described in sea urchin eggs, also operates in mammalian GABAergic neurons. Potentiation of GABA release by NO may have implications for numerous brain functions.
Wang
Sheng
S
Department of Physiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
Teschemacher
Anja G
AG
Paton
Julian F R
JF
Kasparov
Sergey
S
D000818:Animals; D017930:Genes, Reporter; D018698:Glutamic Acid / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006834:Hydrazines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000494:pharmacology; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D017552:Solitary Nucleus / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
D006834:Hydrazines; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D049452:Green Fluorescent Proteins; D009569:Nitric Oxide; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine