Biphasic Coupling of Neuronal Nitric Oxide Synthase Phosphorylation to the NMDA Receptor Regulates AMPA Receptor Trafficking and Neuronal Cell Death

Rameau, Gerald A.; Tukey, David S.; Garcin, Elsa D.; Titcombe, Roseann F.; Misra, Charu; Khatri, Latika; Getzoff, Elizabeth D.; Ziff, Edward B.

doi:10.1523/jneurosci.4799-06.2007

Cited by 146 publications

(143 citation statements)

References 67 publications

(78 reference statements)

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“…7, 23). The CaMKII-mediated regulation of nNOS cannot explain this effect, as CaMKII inhibits rather than activates nNOS (40,43,44). By contrast, the NO-induced CaMKII autonomy indicates that nNOS is instead upstream of CaMKII in excitotoxic death signaling.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Induces Ca2+-independent Activity of the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)

Coultrap

Bayer

2014

Journal of Biological Chemistry

146

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Background: Ca 2ϩ -independent autonomous CaMKII activity and nitric oxide (NO) signaling regulate neuronal function and death. Results: NO generated autonomous CaMKII activity by Ca 2ϩ /CaM-dependent S-nitrosylation, and CaMKII inhibition protected from NO-induced neuronal cell death. Conclusion: NO-mediated regulation of CaMKII contributes to its pathological functions. Significance: S-Nitrosylation is a novel path to CaMKII autonomy that connects Ca 2ϩ -and NO signaling.

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Section: Discussionmentioning

confidence: 99%

Nitric Oxide Induces Ca2+-independent Activity of the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)

Coultrap

Bayer

2014

Journal of Biological Chemistry

146

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“…Our findings establish that PKA also directly phosphorylates and activates nNOS-S1412 in a physiologically meaningful way similar to endothelial PKA phosphorylation of eNOS-S1177 (37). Rameau et al (17,21) used immunofluorescent staining techniques to show that NMDA stimulation of cortical neuronal cultures enhances phosphorylation of nNOS at S1412 in specific and localized synaptic signaling. Conceivably, Akt and PKA phosphorylation of nNOS interact in a regulated fashion.…”

Section: Phospho-protein / Total Proteinmentioning

confidence: 99%

“…nNOS possesses a phosphorylation consensus sequence at S1412 that closely resembles the sequence surrounding eNOS-S1179, and is thought to be a target for Akt in some systems (15)(16)(17)(18)(19)(20)(21). We wondered whether nNOS phosphorylation at S1412 might regulate penile erection.…”

mentioning

confidence: 99%

Cyclic AMP-dependent phosphorylation of neuronal nitric oxide synthase mediates penile erection

Hurt

Sezen²,

Lagoda³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Nitric oxide (NO) generated by neuronal NO synthase (nNOS) initiates penile erection, but has not been thought to participate in the sustained erection required for normal sexual performance. We now show that cAMP-dependent phosphorylation of nNOS mediates erectile physiology, including sustained erection. nNOS is phosphorylated by cAMP-dependent protein kinase (PKA) at serine(S)1412. Electrical stimulation of the penile innervation increases S1412 phosphorylation that is blocked by PKA inhibitors but not by PI3-kinase/Akt inhibitors. Stimulation of cAMP formation by forskolin also activates nNOS phosphorylation. Sustained penile erection elicited by either intracavernous forskolin injection, or augmented by forskolin during cavernous nerve electrical stimulation, is prevented by the NOS inhibitor L-NAME or in nNOS-deleted mice. Thus, nNOS mediates both initiation and maintenance of penile erection, implying unique approaches for treating erectile dysfunction.gasotransmitter | smooth muscle relaxation | endothelial NOS | cyclic GMP | phosphoantibody N itric oxide (NO) is well established as a mediator of penile erection (1, 2). Neuronal NO synthase (nNOS) is highly localized to the penile innervation (3, 4). Electrical stimulation of the cavernous nerve (CN) to the penis elicits penile erection, which is abolished with NOS inhibitors and markedly reduced in nNOS-α-deleted mice (nNOSα −/− ) (5-7). Neuronal depolarizationinduced production of NO reflects calcium entry activating calmodulin associated with nNOS to stimulate NO formation (8,9). This activation is short-lived and thus is believed to account only for the initiation of penile erection (10, 11). Sessa and colleagues (12) established that increased blood flow and associated shear stress, acting via PI3-kinase, augments the activity of the serine protein kinase Akt, which phosphorylates vascular endothelial NOS (eNOS) at serine(S)1179, causing prolonged NO formation at resting intracellular calcium levels (13). The increased penile blood flow through cavernosal vessels initiated by nNOS activation similarly stimulates penile Akt to phosphorylate eNOS, thereby promoting sustained maximal penile erection (14).nNOS possesses a phosphorylation consensus sequence at S1412 that closely resembles the sequence surrounding eNOS-S1179, and is thought to be a target for Akt in some systems (15-21). We wondered whether nNOS phosphorylation at S1412 might regulate penile erection. Using a highly selective antibody for phospho-S1412-nNOS (P-nNOS) we report electrically stimulated nNOS phosphorylation via cAMP-dependent protein kinase (PKA) and not through Akt. P-nNOS activity contributes to sustained erection in concert with phospho-eNOS stimulation, and the neuronal and endothelial NOS activities are independently regulated by separate signaling cascades. We propose a model integrating the posttranslational phospho-stimulation of normal erectile physiology. ResultsElectrical Stimulation of Penile Innervation Augments Phosphorylation of nNOS. We developed a C-terminal ...

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“…47 We previously demonstrated that neuronal-derived NO increased phospho-CREB in cultured retinal cells in an ERK-dependent manner. 23 On the other hand, nNOS activity has been associated with both glutamate-induced excitotoxicity in cortical neurons 48 and AMPA-induced apoptosis in the retina. 15 We showed that calcium influx, nNOS activity and NO production were high in E6 when compared with E8 retinas.…”

Section: Discussionmentioning

confidence: 99%

The nitric oxide-cGKII system relays death and survival signals during embryonic retinal development via AKT-induced CREB1 activation

et al. 2014

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During early neurogenesis, retinal neuronal cells display a conserved differentiation program in vertebrates. Previous studies established that nitric oxide (NO) and cGMP accumulation regulate essential events in retinal physiology. Here we used pharmacological and genetic loss-of-function to investigate the effects of NO and its downstream signaling pathway in the survival of developing avian retinal neurons in vitro and in vivo. Six-day-old (E6) chick retinal cells displayed increased calcium influx and produced higher amounts of NO when compared with E8 cells. L-arginine (substrate for NO biosynthesis) and S-nitroso-N-acetyl-D,L-penicillamine (SNAP; a nitrosothiol NO donor) promoted extensive cell death in E6 retinas, whereas in E8 both substances decreased apoptosis. The effect of NO at both periods was mediated by soluble guanylyl cyclase (sGC) and cGMP-dependent kinase (cGK) activation. In addition, shRNA-mediated cGKII knockdown prevented NO-induced cell death (E6) and cell survival (E8). This, NO-induced cell death or cell survival was not correlated with an early inhibition of retinal cell proliferation. E6 cells also responded differentially from E8 neurons regarding cyclic AMP-responsive element-binding protein (CREB) activation in the retina in vivo. NO strongly decreased nuclear phospho-CREB staining in E6 but it robustly enhanced CREB phosphorylation in the nuclei of E8 neurons, an effect that was completely abrogated by cGKII shRNAs at both embryonic stages. The ability of NO in regulating CREB differentially during retinal development relied on the capacity of cGKII in decreasing (E6) or increasing (E8) nuclear AKT (V-Akt murine thymoma viral oncogene) activation. Accordingly, inhibiting AKT prevented both cGKII shRNA-mediated CREB upregulation in E6 and SNAP-induced CREB activation in E8. Furthermore, shRNAmediated in vivo cGKII or in vitro CREB1 knockdown confirmed that NO/cGKII dualistically regulated the downstream CREB1 pathway and caspase activation in the chick retina to modulate neuronal viability. These data demonstrate that NO-mediated cGKII signaling may function to control the viability of neuronal cells during early retinal development via AKT/CREB1 activity. Cell Death and Differentiation (2014) 21, 915-928; doi:10.1038/cdd.2014.11; published online 14 February 2014The retina is part of the central nervous system (CNS) because of its derivation from the anterior neural tube. Mature retinal tissue is arranged in a laminar structure composed of seven major classes of cells: ganglion, horizontal, amacrine, bipolar, cone and rod photoreceptors and the Mü ller glia. 1 Early retinal tissue is a pseudo-stratified epithelium in which mitotically active neuronal precursor cells are found. Another noteworthy characteristic of vertebrate retinogenesis is the well-established chronology of cell-type generation, with ganglion cells generally being the first cells to be born and the Mü ller glia and bipolar neurons usually the last. Nevertheless, the differentiation periods of different cell type...

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Biphasic Coupling of Neuronal Nitric Oxide Synthase Phosphorylation to the NMDA Receptor Regulates AMPA Receptor Trafficking and Neuronal Cell Death

Cited by 146 publications

References 67 publications

Nitric Oxide Induces Ca2+-independent Activity of the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)

Nitric Oxide Induces Ca2+-independent Activity of the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)

Cyclic AMP-dependent phosphorylation of neuronal nitric oxide synthase mediates penile erection

The nitric oxide-cGKII system relays death and survival signals during embryonic retinal development via AKT-induced CREB1 activation

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