Hydrolysis of N-Methyl-d-aspartate Receptor-Stimulated cAMP and cGMP by PDE4 and PDE2 Phosphodiesterases in Primary Neuronal Cultures of Rat Cerebral Cortex and Hippocampus

Abstract

Stimulation of N-methyl-D-aspartate (NMDA) receptors on neurons activates both cAMP and cGMP signaling pathways. Experiments were carried out to determine which phosphodiesterase (PDE) families are involved in the hydrolysis of the cyclic nucleotides formed via this mechanism, using primary neuronal cultures prepared from rat cerebral cortex and hippocampus. The nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) potentiated the ability of NMDA to increase cAMP and cGMP. However, among the family-selective inhibitors, only the PDE4 inhibitor rolipram enhanced the ability of NMDA to increase cAMP in the neurons. In contrast, only the PDE2 inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) enhanced the ability of NMDA to increase cGMP. Neither adenosine nor an adenosine deaminase inhibitor mimicked the effect of EHNA; this suggests that EHNA's inhibition of PDE2, not its effects on adenosine metabolism, mediates its effects on NMDA-stimulated cGMP concentrations. The PDE inhibitoraugmented effects of NMDA on cAMP and cGMP formation were antagonized by 5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801), verifying NMDA receptor mediation. In contrast, only NMDA-mediated cGMP formation was affected by altering either nitric oxide signaling or guanylyl cyclase; this suggests that NMDA-induced changes in cAMP are not secondary to altered cGMP concentrations. Overall, the present findings indicate that cAMP and cGMP formed in neurons as a result of NMDA receptor stimulation are hydrolyzed by PDE4 and PDE2, respectively. Selective inhibitors of the two PDE families will differentially affect the functional consequences of activation of these two signaling pathways by NMDA receptor stimulation.

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

“…In fact, future studies will explore if rolipram is able to reverse the cognitive deficits exhibited by Gas transgenic mice (Kelly et al, 2003). Further, given the role of PDE4 in NMDA receptor signaling (eg Suvarna and O'Donnell, 2002), future studies will also examine the potential role of hypoglutamatergic functioning in Gasinduced behavioral and biochemical deficits. It is important to note that, in rodent models, rolipram combats the detrimental motoric side effects of long-term haloperidol administration (Sasaki et al, 1995).…”

Pituitary Adenylate Cyclase-activating Polypeptide (PACAP(1–38)) Enhances N-Methyl-d-aspartate Receptor Function and Brain-derived Neurotrophic Factor Expression via RACK1

“…Several reports suggest a link among RACK1, cAMP signaling, and NMDA receptors. Yarwood et al (30) identified a direct interaction between RACK1 and the cAMP-specific phosphodiesterase 4 isoform phosphodiesterase 5 (30), and recently phosphodiesterase 4 was found to regulate the function of the NMDA receptor and thus is likely to be part of the postsynaptic density complex as well (31). Moreover, several reports suggest a link between cAMP/PKA signaling and the phosphorylation state and activity of the NMDA receptor channel.…”

Inhibition of the Phosphodiesterase 4 (PDE4) Enzyme Reverses Memory Deficits Produced by Infusion of the MEK Inhibitor U0126 into the CA1 Subregion of the Rat Hippocampus

“…PDE4 has been shown to be an important mediator of memory processes associated with N-methyl-D-aspartate (NMDA) receptor-mediated signaling. Pretreatment with rolipram, a PDE4-selective inhibitor, reverses the amnesic effect of the NMDA receptor antagonist MK-801 in rats and enhances NMDA-induced increases in cAMP in rat cerebral cortical neurons Suvarna and O'Donnell, 2002). This is supported by recent findings that rolipram blocks memory deficits induced by heterozygous deficiency of cAMP-responsive element binding protein (CREB)-binding protein (CBP; Bourtchouladze et al, 2003), and that PDE4 is involved in the induction of long-term potentiation (LTP) in the CA1 subregion of the hippocampus (Ahmed and Frey, 2003), an area where PDE4 is highly expressed (McPhee et al, 2001).…”