The NO/cGMP pathway inhibits transient cAMP signals through the activation of PDE2 in striatal neurons

Marina Polito,Kees Jalink,Liliana R.V Castro,Pierre Vincent,Danièle Paupardin-Tritsch,Jeffrey Klarenbeek

doi:10.3389/fncel.2013.00211

Abstract

The NO-cGMP signaling plays an important role in the regulation of striatal function although the mechanisms of action of cGMP specifically in medium spiny neurons (MSNs) remain unclear. Using genetically encoded fluorescent biosensors, including a novel Epac-based sensor (EPAC-SH150) with increased sensitivity for cAMP, we analyze the cGMP response to NO and whether it affected cAMP/PKA signaling in MSNs. The Cygnet2 sensor for cGMP reported large responses to NO donors in both striatonigral and striatopallidal MSNs, this cGMP signal was controlled partially by PDE2. At the level of cAMP brief forskolin stimulations produced transient cAMP signals which differed between D1 and D2 MSNs. NO inhibited these cAMP transients through cGMP-dependent PDE2 activation, an effect that was translated and magnified downstream of cAMP, at the level of PKA. PDE2 thus appears as a critical effector of NO which modulates the post-synaptic response of MSNs to dopaminergic transmission.

Highlights

Cyclic nucleotides control a range of cellular processes, in neurons where they transduce extracellular signals carried by neuromodulators
The functional effects of the cAMP signaling cascade has been widely documented in the striatum (Hervé and Girault, 2005) but much less is know about the cGMP signaling. cGMP is produced by the NO receptor, aka soluble guanylyl cyclase, in response to nitric oxide (NO), and NO/cGMP signaling regulates a number of neurobiological processes (Garthwaite, 2008). sGC is highly expressed in the striatum (Ariano et al, 1982; Matsuoka et al, 1992; Ding et al, 2004) while the NO producing enzyme nNOS is highly expressed by a fraction of striatal interneurons (Vincent and Kimura, 1992; Rushlow et al, 1995; Kawaguchi, 1997; Vincent, 2000)
Our data demonstrate the functional importance of PDE2 as a target of the NO/cGMP pathway, and its importance in the regulation of transient cAMP responses

Summary

Introduction

Cyclic nucleotides control a range of cellular processes, in neurons where they transduce extracellular signals carried by neuromodulators. Medium spiny neurons (MSNs) in the striatum constitute 95% of the neuronal types, approximately half of which are anatomically defined as the “direct pathway” and express dopamine type 1 receptors (D1) This receptor is positively coupled to cAMP production. NO diffuses into the dendrites of MSNs modulating corticostriatal synaptic plasticity in vitro (Calabresi et al, 1999, 2000) and in vivo (West and Grace, 2004) While these effects are clearly mediated by cGMP, the downstream effectors of cGMP, often assumed to be the cGMP-dependent protein kinase (PKG), remain uncertain, since only moderate levels of expression have been reported in the striatum (el-Husseini et al, 1995; El-Husseini et al, 1999; de Vente et al, 2001) and CNG expression has not been reported in the striatum (Wei et al, 1998)

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