Phorbol esters enhance transmitter release in rat hippocampal slices

Malenka, Robert C.; Ayoub, George; Nicoll, Roger A.

doi:10.1016/0006-8993(87)90145-4

Cited by 225 publications

(94 citation statements)

References 25 publications

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“…Thus, taken together, our findings are consistent with a PKC-dependent activation of NADPH oxidase in the hippocampal neurons after treatment with PMA. It is well known that incubation of hippocampal slices with phorbol esters increases synaptic transmission (Malenka et al, 1986(Malenka et al, ,1987Parfitt and Madison, 1993). Therefore, our findings also suggest the possibility that production of superoxide via NADPH oxidase contributes to phorbol ester-induced increases in synaptic transmission in hippocampal slices.…”

Section: Discussionsupporting

confidence: 75%

Synaptic localization of a functional NADPH oxidase in the mouse hippocampus

Tejada‐Simon

Serrano

Villasana

et al. 2005

Molecular and Cellular Neuroscience

195

154

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Superoxide has been shown to be critical for hippocampal long-term potentiation (LTP) and hippocampus-dependent memory function. A possible source for the generation of superoxide during these processes is NADPH oxidase. The active oxidase consists of two membrane proteins, gp91 phox and p22 phox , and four cytosolic proteins, p40 phox , p47 phox , p67 phox , and Rac. Upon stimulation, the cytosolic proteins translocate to the membrane to form a complex with the membrane components, which results in production of superoxide. Here, we determined the presence, localization, and functionality of a NADPH oxidase in mouse hippocampus by examining the NADPH oxidase proteins as well as the production of superoxide. All of the NADPH oxidase proteins were present in hippocampal homogenates and enriched in synaptoneurosome preparations. Immunocytochemical analysis of cultured hippocampal neurons indicated that all NADPH oxidase proteins were localized in neuronal cell bodies as well as dendrites. Furthermore, double labeling analysis using antibodies to p67 phox and the presynaptic marker synaptophysin suggest a close association of the NADPH oxidase subunits with synaptic sites. Finally, stimulation of hippocampal slices with phorbol esters triggered translocation of the cytoplasmic NADPH oxidase proteins to the membrane and an increase in superoxide production that was blocked by inhibitors of NADPH oxidase. Taken together, our data suggest that NADPH oxidase is present in mouse hippocampus and might be the source of superoxide production required for LTP and memory function.

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Section: Discussionsupporting

confidence: 75%

Synaptic localization of a functional NADPH oxidase in the mouse hippocampus

Tejada‐Simon

Serrano

Villasana

et al. 2005

Molecular and Cellular Neuroscience

195

154

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“…Phorbol esters and diacylglycerol can release hormone and other transmitters from secretory elements (Nishizuka, 1984), including nerve terminals (Wakade et al, 1985;Eusebi et al, 1986;Haimann et al, 1987;Malenka et al, 1987;Nichols et al, 1987;Shapira et al, 1987). Because this release can occur in a Caindependent way (Nishizuka, 1984;Malenka et al, 1987), it is not possible in a multicellular preparation such as a brain slice or tissue culture to exclude the possibility that PKC activators…”

Section: Discussionmentioning

confidence: 99%

“…Because this release can occur in a Caindependent way (Nishizuka, 1984;Malenka et al, 1987), it is not possible in a multicellular preparation such as a brain slice or tissue culture to exclude the possibility that PKC activators…”

Section: Discussionmentioning

confidence: 99%

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Protein kinase C activators block specific calcium and potassium current components in isolated hippocampal neurons

1988

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Whole-cell voltage-clamp techniques were used to study the effects of the protein kinase C (PKC) activators phorbol esters and OAG on Ca and K currents in differentiated neurons acutely dissociated from adult hippocampus and in tissue-cultured neurons from fetal hippocampus. PKC activators had selective depressant effects on K currents, with persistent currents (IK and IK-Ca) being reduced and transient current (IA) being unaffected. In both cell types we recorded both high-voltage- activated, noninactivating (L-type) and high-voltage-activated, rapidly inactivating (N-type) Ca current. A low-voltage-activated, rapidly inactivating (T-type) Ca current was also recorded in tissue-cultured neurons but not in acutely dissociated neurons. PKC activators markedly reduced N-type current with less effect on L-type and no effect on T- type Ca current. Effects of PKC activators could be reversed with washing or with application of PKC inhibitors H-7 or polymyxin-B, an effect that could not be attributed to inhibition of cAMP-dependent protein kinase. The Ca/calmodulin inhibitor calmidazolium was ineffective in reversing the actions of PKC activators. Using whole- cell voltage-clamp techniques, we have demonstrated that hippocampal neurons possess 3 distinguishable components of calcium current. Distinct K currents were also observed. Our data strongly support the hypothesis that both Ca and K currents are selectively regulated by PKC and that these effects occur directly on the postsynaptic neuron.

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“…30). In particular, it has clearly been shown that activation of PKC by phorbol esters can lead to an enhancement of L-glutamate release (31)(32)(33)(34). Several studies indicate that PKC translocation from cytosol to membrane is associated with both PKC activation and enhanced L-glutamate release (32,35,36).…”

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confidence: 99%

Phosphorylation of the N-Ethylmaleimide-sensitive Factor Is Associated with Depolarization-dependent Neurotransmitter Release from Synaptosomes

Matveeva¹,

Whiteheart²,

Vanaman³

et al. 2001

Journal of Biological Chemistry

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Critical to SNARE protein function in neurotransmission are the accessory proteins, soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP), and NSF, that play a role in activation of the SNAREs for membrane fusion. In this report, we demonstrate the depolarization-induced, calcium-dependent phosphorylation of NSF in rat synaptosomes. Phosphorylation of NSF is coincident with neurotransmitter release and requires an influx of external calcium. Phosphoamino acid analysis of the radiolabeled NSF indicates a role for a serine/threonine-specific kinase. Synaptosomal phosphorylation of NSF is stimulated by phorbol esters and is inhibited by staurosporine, chelerythrine, bisindolylmaleimide I, calphostin C, and Ro31-8220 but not the calmodulin kinase II inhibitor, Kn-93, suggesting a role for protein kinase C (PKC). Indeed, NSF is phosphorylated by PKC in vitro at Ser-237 of the catalytic D1 domain. Mutation of this residue to glutamic acid or to alanine eliminates in vitro phosphorylation. Molecular modeling studies suggest that Ser-237 is adjacent to an inter-subunit interface at a position where its phosphorylation could affect NSF activity. Consistently, mutation of Ser-237 to Glu, to mimic phosphorylation, results in a hexameric form of NSF that does not bind to SNAP-SNARE complexes, whereas the S237A mutant does form complex. These data suggest a negative regulatory role for PKC phosphorylation of NSF. The molecular mechanisms of neurotransmitter (NT)1 release have been the subject of much attention in recent years resulting in an evolving model known as the SNARE hypothesis (1-3). The SNARE hypothesis holds that membrane proteins in the vesicle (v-SNAREs, e.g. synaptobrevins) bind to a heterodimer in the target membrane (t-SNAREs, heterodimers of syntaxins and SNAP-25-like proteins). v-and t-SNAREs bind to form a 7 S complex (1, 4), composed of a bundle of four parallel, coiled-coil domains (5-8) that, through reconstitution studies, has been demonstrated to be minimally required for bilayer fusion (9). The N-ethylmaleimide-sensitive factor (NSF) and the soluble NSF attachment proteins (SNAPs, not to be confused with SNAP-25) affect the composition and structure of the SNARE complex. SNAPs act as adapters and are required for binding of NSF to the 7 S complex. ATP hydrolysis by NSF causes the resulting 20 S complex to disassemble into monomeric SNAREs (4, 10), a step required for vesicle trafficking (11-13). Detailed kinetic experiments have placed one role of NSF and SNAPs at steps prior to v-/t-SNARE binding (14 -16), suggesting a model in which NSF disassembles cis 7 S complexes that exist in the same bilayer (17-19). The resulting monomeric SNAREs can then form trans 7 S complexes that span the opposing bilayers of the vesicle and target membrane. In this manner, NSF acts as a chaperone to activate or "prime" the SNARE proteins for subsequent trans complex formation and membrane fusion.Studies by Schweizer et al. (20), using NSF-derived peptides microinjected pre-synaptically, showed that ...

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Phorbol esters enhance transmitter release in rat hippocampal slices

Cited by 225 publications

References 25 publications

Synaptic localization of a functional NADPH oxidase in the mouse hippocampus

Synaptic localization of a functional NADPH oxidase in the mouse hippocampus

Protein kinase C activators block specific calcium and potassium current components in isolated hippocampal neurons

Phosphorylation of the N-Ethylmaleimide-sensitive Factor Is Associated with Depolarization-dependent Neurotransmitter Release from Synaptosomes

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