Expression of cGMP-Specific Phosphodiesterase 9A mRNA in the Rat Brain

Abstract

cGMP has been implicated in the regulation of many essential functions in the brain, such as synaptic plasticity, phototransduction, olfaction, and behavioral state. Cyclic nucleotide phosphodiesterase (PDE) hydrolysis of cGMP is the major mechanism underlying the clearance of cGMP and is likely to be important in any process that depends on intracellular cGMP. PDE9A has the highest affinity for cGMP of any PDE, and here we studied the localization of this enzyme in the rat brain using in situ hybridization. PDE9A mRNA is widely distributed throughout the brain with varying regional expression. The pattern of PDE9A mRNA expression closely resembles that of soluble guanylyl cyclase (sGC) in the rat brain, suggesting a possible functional association or coupling of these two enzymes in the regulation of cGMP levels. Most of the brain areas expressing PDE9A mRNA also contain neuronal nitric oxide synthase (NOS), the enzymatic source of NO and the principal activator of sGC. PDE9A is the only cGMP-specific PDE with significant expression in the forebrain, and as such is likely to play an important role in NO-cGMP signaling.

Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use

“…Although PDE9A mRNA is widely expressed in mouse and rat brain, it has a distribution pattern of varying intensity. Two studies have found PDE9A mRNA expression to vary by region but agree that the highest levels are in the olfactory bulb, dentate gyrus, Purkinje cells, and olfactory tubercle (Andreeva et al, 2001;Van Staveren et al, 2002). Expression was considered to be predominantly neuro- FIG.…”

“…No studies clearly elucidating a specific function for PDE9A have been published to date. However, the finding that PDE9A localizes to rat brain areas also expressing soluble guanylyl cyclase and neuronal nitric oxide synthase suggests that it may regulate cGMP signaling in these regions (Andreeva et al, 2001). Recently, the compound BAY 73-6691 has been reported as a potent (IC 50 55 nM) cell permeable PDE9 selective inhibitor (Wunder et al, 2005).…”

A novel role for cyclic guanosine 3′,5′monophosphate signaling in synaptic plasticity: A selective suppressor of protein kinase A-dependent forms of long-term potentiation

“…Thus, to determine whether cGMP signaling can regulate the induction of PKA-dependent forms of LTP we examined whether TPS-induced LTP was altered in slices bathed in ACSF containing the cGMP-specific phosphodiesterase inhibitor zaprinast (ZAP), a compound previously shown to elevate cGMP levels in hippocampal slices (Boulton et al, 1994). Because hippocampal pyramidal cells express two distinct cGMP-specific phosphodiesterases (PDE5 and PDE9) (Andreeva et al, 2001;Van Staveren et al, 2003) with different sensitivities to ZAP (IC50s of 0.76 and 29 μM, respectively) (Soderling et al, 1998), ZAP was bath applied at a concentration of 50 μM to effectively inhibit both isoforms.…”

“…Thus, to determine whether cGMP signaling can regulate the induction of PKA-dependent forms of LTP we examined whether TPS-induced LTP was altered in slices bathed in ACSF containing the cGMP-specific phosphodiesterase inhibitor zaprinast (ZAP), a compound previously shown to elevate cGMP levels in hippocampal slices (Boulton et al, 1994). Because hippocampal pyramidal cells express two distinct cGMP-specific phosphodiesterases (PDE5 and PDE9) (Andreeva et al, 2001;Van Staveren et al, 2003) with different sensitivities to ZAP (IC50s of 0.76 and 29 μM, respectively) (Soderling et al, 1998), ZAP was bath applied at a concentration of 50 μM to effectively inhibit both isoforms.Consistent with previous reports (Boulton et al, 1994;Broome et al, 1994;Wu et al, 1998;Santschi et al, 1999), ZAP induced a significant depression of basal synaptic transmission that persisted for as long as ZAP was present in the bath (Fig. 1A, 60 min after the start of ZAP application fEPSPs were reduced to 63±3% of baseline, n=5, P<0.001 compared with baseline).…”

Crosstalk between G-protein and Ca2+ pathways switches intracellularcAMP levels

“…PDEIX has the highest affinity for cGMP and has been proposed as a regulator of cGMP signaling. 26,27 PDEX is not as well characterized as some other PDE families. However, it has been reported that PDEX is more cAMP rather than cGMP specific.…”