The PSD-95/nNOS complex: New drugs for depression?

Doucet, Marika; Harkin, Andrew; Dev, Kumlesh K.

doi:10.1016/j.pharmthera.2011.11.005

Cited by 70 publications

(58 citation statements)

References 122 publications

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“…In addition, while SERT is distributed pre-synaptically, PSD-95 is localised at the postsynaptic density. It therefore seems unlikely that the PSD-95/nNOS inhibitor IC87201 will disrupt the SERT/nNOS interaction (for a review, see Doucet et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…The presumed mode of action of these compounds would be a somewhat region-selective disruption of the NMDA-R/PSD-95/nNOS complex in the hippocampus, while eg, NO signalling in the basal ganglia, cerebellum and amygdala should remain unchanged. Our approach to assessing this potential is to develop lentiviral tools constructed to deliver genetic material for region specific and sustained expression of a 'nNOS decoy' peptide designed to interrupt interaction between nNOS and PSD-95 (see Doucet et al, 2012). Data generated in the laboratory thus far indicate that delivery of the decoy to the prefrontal cortex fails to produce antidepressant-related activity (forced swim test-related mobility) in rats.…”

Section: Discussionmentioning

confidence: 99%

“…The postsynaptic density protein 95 kDa (PSD-95) is a scaffolding protein that links nNOS to NMDA-R. Disruption of the PSD-95/nNOS interaction has been achieved with both peptide fragments and small-molecule inhibitors (for review see Doucet et al, 2012). As other functions of the NMDA receptor remain intact, this selective approach may be adopted to further test for a novel glutamatergic NObased treatment for depression.…”

Section: Introductionmentioning

confidence: 99%

“…As NMDA receptors couple to nNOS via the postsynaptic protein PSD-95, inhibition of PSD-95/nNOS may elicit an antidepressant response with a better side-effect profile (Doucet et al, 2012). To further explore this hypothesis, the present investigation assessed compounds targeting the PSD-95/nNOS interface, IC87201 and ZL006 for antidepressant effects in the mouse tail suspension test (TST) and FST.…”

Section: Introductionmentioning

confidence: 99%

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Small-Molecule Inhibitors at the PSD-95/nNOS Interface have Antidepressant-Like Properties in Mice

Doucet

Levine

Dev

et al. 2013

Neuropsychopharmacol

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Previous studies have demonstrated that nitric oxide (NO) synthase inhibitors are as efficacious as tricyclic antidepressants in preclinical antidepressant screening procedures and in attenuating behavioural deficits associated with animal models of depression. The N-methyl-D-aspartate receptor (NMDA-R) complex gates Ca 2 þ , which interacts with calmodulin to subsequently activate NO synthase. We hypothesised that uncoupling neuronal nitric oxide synthase (nNOS) from the NMDA-R through the scaffolding protein postsynaptic density protein 95 (PSD-95) would produce behavioural antidepressant effects similar to NO synthase inhibitors. Small-molecule inhibitors of the PSD-95/nNOS interaction, IC87201 (0.01-2 mg/kg) and ZL006 (10 mg/kg) were tested for antidepressant properties in tests of antidepressant activity namely the tail suspension and forced swim tests in mice. We now report that IC87201 and ZL006 produce antidepressant-like responses in the forced swimming test (FST) and tail suspension test (TST) following a single administration in mice. By contrast to the tricyclic antidepressant imipramine (25 mg/kg), the effects are not observed 1 h following drug administration but are apparent 24 and 72 h later. Furthermore prior exposure to the TST or FST is required in order to observe the antidepressantrelated activity. Similar delayed and sustained antidepressant-like effects were observed following TRIM (50 mg/kg) and ketamine (30 mg/kg) in the TST. The antidepressant-like effects of ZL006 also generalise to IC87201 in the TST. IC87201 was devoid of effects on locomotor activity and step-through latency in the passive avoidance cognition test. These data support the hypothesis that targeting the PSD-95/nNOS interaction downstream of NMDA-R produces antidepressant effects and may represent a novel class of therapeutics for major depressive disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Small-Molecule Inhibitors at the PSD-95/nNOS Interface have Antidepressant-Like Properties in Mice

Doucet

Levine

Dev

et al. 2013

Neuropsychopharmacol

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“…Here we have further revealed that APPL1 binds to the PDZ2 domain of PDD95. Interestingly, the PDZ2 domain of PSD95 interacts with a large number of proteins, including NMDARs, Sema 4f, APC, and nNOS [18]. Accumulating evidence has demonstrated that recruitment of the Ca 2?…”

Section: Appl1 S707a Disrupts Synaptic Activity-mediated Activation Omentioning

confidence: 99%

Serine 707 of APPL1 is Critical for the Synaptic NMDA Receptor-Mediated Akt Phosphorylation Signaling Pathway

Wang

Chen

et al. 2016

Neurosci. Bull.

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Accumulating evidence indicates that the synaptic activation of N-methyl-D-aspartate receptors (NMDARs) has a neuroprotective effect on neurons. Our previous study demonstrated that APPL1 (adaptor protein containing pleckstrin homology domain, phosphotyrosinebinding domain, and leucine zipper motif) mediates the synaptic activity-dependent activation of PI3K-Akt signaling via coupling this pathway with NMDAR-PSD95 (postsynaptic density protein 95) complexes. However, the molecular mechanism underlying this process is still unknown. In the present study, we investigated the interaction of APPL1 with PSD95 using co-immunocytochemical staining and western blotting. We found that the PDZ2 domain of PSD95 is a binding partner of APPL1. Furthermore, we identified serine 707 of APPL1, a predicted phosphorylation site within the PDZ-binding motif at the C-terminus, as critical for the binding of APPL1 to PSD95, as well as for activation of the Akt signaling pathway during synaptic activity. This suggests that serine 707 of APPL1 is a potential phosphorylation site and may be involved in regulating the neuroprotective Akt signaling pathway that depends on synaptic NMDAR activity.

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Employment of Molecularly Imprinted Polymers to High‐Throughput Screen nNOS‐PSD‐95 Interruptions: Structure and Dynamics Investigations on Monomer–Template Complexation

et al. 2016

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Molecularly imprinted polymers (MIPs) are employed to screen nNOS-PSD-95 (neuronal nitric oxide synthase post-synaptic density protein-95) interruptions. 5-(3,5-Dichloro-2-hydroxybenzylamino)-2-hydroxybenzoic acid (ZL006; a potential drug candidate for the treatment of stroke, depression, and pain) is employed as a template. Four kinds of functional monomers (2-VP: 2-vinylpyridine; 4-VP: 4-vinylpyridine; MMA: methyl methacrylate; and MAAM: methacrylamide) are designed, and their complexation with ZL006 in various solvents (methanol, acetonitrile, toluene, chloroform) is investigated by molecular dynamics simulations and quantum mechanics calculations. Both 4-VP and MAAM have stronger interactions with ZL006 than those of 2-VP and MMA. The appropriate ratio of monomer to template is 3:1. Intermolecular hydrogen bonds play a dominant role in monomer-template complexation. Ideal solvents are toluene and chloroform, and the solvation effect on monomer-template complexation is revealed. Both molecular modeling and adsorption experiments demonstrate that as-synthesized ZL006-MIP with 4-VP as a monomer has better selectivity than that employing MAAM to screen for nNOS-PSD-95 interruptions.

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The PSD-95/nNOS complex: New drugs for depression?

Cited by 70 publications

References 122 publications

Small-Molecule Inhibitors at the PSD-95/nNOS Interface have Antidepressant-Like Properties in Mice

Small-Molecule Inhibitors at the PSD-95/nNOS Interface have Antidepressant-Like Properties in Mice

Serine 707 of APPL1 is Critical for the Synaptic NMDA Receptor-Mediated Akt Phosphorylation Signaling Pathway

Employment of Molecularly Imprinted Polymers to High‐Throughput Screen nNOS‐PSD‐95 Interruptions: Structure and Dynamics Investigations on Monomer–Template Complexation

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