Signalling pathway of nitric oxide in synaptic GABA release in the rat paraventricular nucleus

Abstract

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. Wholecell 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 Ca 2+ with Co 2+ nor application of Cd 2+ to block the Ca 2+ channel altered the effect of SNAP on mIPSCs. Also, the effect of SNAP on mIPSCs was not significantly affected by thapsigargin, a Ca 2+ -ATPase inhibitor that depletes intracellular Ca 2+ 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.

Nitric oxide regulates synaptic transmission between spiny projection neurons

“…guanylyl cyclase | vesicular GABA transporter | BacTRAP | spiny projecting neurons | axon collaterals T hroughout the CNS, the volume transmitter nitric oxide (NO) has been implicated in modulating synaptic function, including transmitter release and plasticity (1,2). The primary target of NO is soluble guanylyl cyclase (sGC), a heterodimer comprising α and β subunits.…”

Role of GABA receptors in nitric oxide inhibition of dorsolateral periaqueductal gray neurons

“…Considering 100 μM of SNAP perfused into the recording chamber, NO may also affect other pathways. A previous study using patch methods has shown that 100 μM SNAP increases GABA release from presynaptic sites through sGCcGMP-protein kinase G in the hypothalamic slice (Li et al, 2003).…”

“…1G&H), indicating that no desensitization to SNAP had occurred. Finally, on the basis of previous reports (Li et al 2003;Wang et al 2006) 20 μM of ODQ, the soluble guanylate cyclase (sGC) inhibitor, was perfused into the recording chamber for 20 min (Fig. 1J&K, n=6).…”

Antagonism by NOS Inhibition of the Behavioral Effects of Benzodiazepine and GABAA Receptor Agonists in the Mouse Elevated Plus-Maze

“…The scientific literature does contain evidence for interaction between GABA and NO, but the majority of such studies focus on NO modulation of the neuronal release of GABA (Wall, 2003;Li et al, 2004). However, a recent study demonstrated that activation of GABA A receptors by muscimol or activation of the benzodiazepine binding site by diazepam increases the population of nNOSpositive cells in the frontal and parietal areas of the developing cortex (Mantelas et al, 2003).…”