Activity-dependent liberation of synaptic neuropeptide vesicles

Shakiryanova, Dinara; Tully, Arvonn; Hewes, Randall S.; Deitcher, David L.; Levitan, Edwin S.

doi:10.1038/nn1377

Cited by 110 publications

(142 citation statements)

References 37 publications

Supporting

Mentioning

133

Contrasting

Unclassified

Order By: Relevance

“…1 B and C, closed circles). Indeed, this release was comparable to that seen with minutes of intense electrical activity in the presence of extracellular Ca 2+ (13). The inactive analog dideoxyforskolin did not mimic this response (Fig.…”

Section: Resultssupporting

confidence: 52%

“…AnfGFP fluorescence was detected with wide-field epifluorescence microscopy in muscle 6 and 7 type Ib boutons of elav-GAL4 UAS-AnfGFP flies using an Olympus BX microscope equipped with a 60× 1.1 NA water-immersion objective, fluorescein filters, and a Hamamatsu digitalcooled CCD camera, as described previously (13,19). The same optics were used to measure Ca 2+ in flies generated by crossing Ok6-GAL4 with UASGCaMP3 (24), which were kindly provided by Loren Looger (Janelia Farm, Ashburn, VA).…”

Section: Methodsmentioning

confidence: 99%

“…Similarly, presynaptic expression of the dominant-negative PKA subunit was accomplished with single crosses of BDK22 and BDK35 flies (20), which were kindly provided by Daniel Kalderon (Columbia University, New York, NY), to flies expressing AnfGFP driven by elav-Gal4 or Geneswitch 3550-2 with RU486 feeding (28,29). Nerve stimulation was performed in Ca 2+ -free HL3 or Ca 2+ -containing HL3, as described previously (13,19). Inhibitors of signaling, such as H89, Tg, Xesto, and Ryan, were applied for 15 to 25 min before application of octopamine or FSK.…”

Section: Methodsmentioning

confidence: 99%

“…Octopamine is also in NMJ boutons at muscles 12 and 13 and can have complex effects at adjacent muscle 6 and 7 NMJs: octopamine inhibits phasic transmission and facilitates tonic release induced by K + , with the latter effect requiring cAMP-dependent protein kinase (PKA) (6)(7)(8). Drosophila motoneurons also contain neuropeptides, which are released in response to nerve stimulation, depolarization, and developmental cues (9)(10)(11)(12)(13). However, the impact of octopamine and cAMP on synaptic neuropeptide release is unknown, even though such regulation could be relevant to the effects of octopamine on central peptidergic neurons involved in controlling metabolism, development, and circadian behavior (14,15).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Synaptic neuropeptide release induced by octopamine without Ca ²⁺ entry into the nerve terminal

Shakiryanova

Zettel

et al. 2011

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

Self Cite

View full text Add to dashboard Cite

Synaptic release of neurotransmitters is evoked by activity-dependent Ca 2+ entry into the nerve terminal. However, here it is shown that robust synaptic neuropeptide release from Drosophila motoneurons is evoked in the absence of extracellular Ca 2+ by octopamine, the arthropod homolog to norepinephrine. Genetic and pharmacology experiments demonstrate that this surprising peptidergic transmission requires cAMP-dependent protein kinase, with only a minor contribution of exchange protein activated by cAMP (epac). Octopamine-evoked neuropeptide release also requires endoplasmic reticulum Ca 2+ mobilization by the ryanodine receptor and the inositol trisphosphate receptor. Hence, rather than relying exclusively on activity-dependent Ca 2+ entry into the nerve terminal, a behaviorally important neuromodulator uses synergistic cAMP-dependent protein kinase and endoplasmic reticulum Ca 2+ signaling to induce synaptic neuropeptide release.N euromodulators induce presynaptic signaling to regulate fast neurotransmission triggered by activity-induced Ca 2+ entry into the nerve terminal. Neuromodulators also influence the very low rate of spontaneous quantal release of classical transmitters. However, because spontaneous release is functionally relevant only in specialized cases (1), neuromodulators are not believed to typically induce physiologically significant release in the absence of extracellular Ca 2+ . Studies of endocrine cells suggest that release of peptides packaged in large dense-core vesicles (LDCVs) also requires Ca 2+ entry because of the rarity of spontaneous LDCV fusion and the inefficient permeation of peptides through the LDCV-fusion pore (2, 3). However, because it is difficult to measure peptide release at intact synapses, a much more limited dataset supports the conclusion that Ca 2+ influx into the nerve terminal is absolutely required for peptidergic transmission. Thus, it remains unclear how neuromodulators control synaptic neuropeptide release.With this background in mind, we set out to study regulation of neuropeptide release at the Drosophila neuromuscular junction (NMJ) by octopamine-induced cAMP signaling. Octopamine, the homolog of norepinephrine in Drosophila, controls many behaviors by activating central G protein-coupled receptors that induce adenylyl cyclase activation and intracellular Ca 2+ release (4, 5).

show abstract

Section: Resultssupporting

confidence: 52%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Synaptic neuropeptide release induced by octopamine without Ca ²⁺ entry into the nerve terminal

Shakiryanova

Zettel

et al. 2011

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…F-actin had been speculated to either hinder vesicles directly, to act as a scaffold for tethering vesicles or to provide a track for regulated motors. However, depolymerizing F-actin does not mimic or prevent activity-induced mobilization of DCVs or SSVs (2)(3)(4). The first indication that synapsin is also not essential came with the observation of DCV mobilization in type III Drosophila NMJ boutons (2), which do not have detectable synapsin (6).…”

Section: B F-actin and Synapsin Are Not Involved In Mobilizationmentioning

confidence: 99%

Signaling for Vesicle Mobilization and Synaptic Plasticity

Levitan

2008

Mol Neurobiol

View full text Add to dashboard Cite

The hypothesis that release of classical neurotransmitters and neuropeptides is facilitated by increasing the mobility of small synaptic vesicles (SSVs) and dense core vesicles (DCVs) could not be tested until the advent of methods for visualizing these secretory vesicles in living nerve terminals. In fact, fluorescence imaging studies have only since 2005 established that activity increases secretory vesicle mobility in motoneuron terminals and chromaffin cells. Mobilization of DCVs and SSVs appears to be due to liberation of hindered vesicles to promote quicker diffusion. However, Factin and synapsin, which have been featured in mobilization models, are not required for activitydependent increases in the mobility of DCVs or SSVs. Most recently, the signaling required for sustained mobilization has been identified for Drosophila motoneuron DCVs and shown to increase synaptic transmission. Specifically, presynaptic endoplasmic reticulum ryanodine receptor (RyR)-mediated Ca 2+ release activates Ca 2+ /calmodulin-dependent kinase II (CamKII) to mobilize DCVs and induce post-tetanic potentiation (PTP) of neuropeptide release in the Drosophila neuromuscular junction. The shared signaling for increasing vesicle mobility and PTP links vesicle mobilization and synaptic plasticity. KeywordsSynaptic vesicle; Dense core vesicle; Release; Exocytosis; Neuropeptide; Mobility It has long been speculated that neurotransmission is facilitated by increasing synaptic vesicle mobility. For example, it was hypothesized that liberation of small synaptic vesicles (SSVs) tethered to F-actin by synapsin regulates transmitter release (1). However, without direct observation of regulated vesicle mobility in nerve terminals, the meaning of the term "mobilization" broadened to encompass any process that increases release. This vagueness arose because an activity-dependent increase in vesicle mobility (i.e., what is meant by "mobilization" for the rest of this review) was not detected directly until the advent of approaches for labeling vesicles with GFP (Green Fluorescent Protein) and FM1-43 (a styryl dye) so that vesicle motion could be monitored directly in living cells with fluorescence microscopy. Here we describe the recent insights made with live cell imaging that link the signaling that increases vesicle mobility in the nerve terminal to synaptic plasticity. A. Vesicle mobilization by liberationActivity-dependent vesicle mobilization in a native nerve terminal was first demonstrated with neuropeptide-containing dense core vesicles (DCVs) in the Drosophila neuromuscular junction (NMJ) (2). In that case, DCV mobility is increased for minutes following seconds of electrical activity. A year and a half later stimulation was found to mobilize chromaffin cell DCVs and frog NMJ SSVs (3,4). Mobilized secretory vesicles appear to move randomly with little sensitivity to temperature (2-4). These observations are in accord with the earlier demonstration that releasable and reserve vesicles move by diffusion, but at different rates corr...

show abstract

Enkephalin co‐expression with classic neurotransmitters in the amygdaloid complex of the rat

Poulin

Castonguay-Lebel

Laforest

et al. 2007

J of Comparative Neurology

View full text Add to dashboard Cite

This study aimed at characterizing the neurotransmitter phenotype of enkephalin neurons in the rat amygdaloid complex. We first established the detailed distribution of vesicular glutamate transporters 1 and 2 (VGLUT1 and -2) and glutamate decarboxylase 65 (GAD65) in the amygdala by using in situ hybridization. In the amygdaloid complex, GAD65 is strongly expressed in striatal-like divisions, namely, the anterior amygdaloid area, the central nucleus (CEA), the intercalated nuclei, and the dorsal part of the medial nucleus (MEA). VGLUT1 and -2 expression is mostly segregated to specific divisions of the amygdale, with VGLUT2 being expressed only in the MEA, the anterior cortical nucleus (COAa), and the anterior basomedial nucleus (BMAa), whereas VGLUT1 is expressed in all other divisions of the amygdala. Second, we assessed the co-expression of preproenkephalin (ppENK) with GAD65, VGLUT1, or VGLUT2 by using double fluorescent in situ hybridization. We found that ppENK mRNA co-localized exclusively with GAD65 in all striatal-like structures of the amygdaloid complex with the exception of the MEA, where ENK also co-localized with VGLUT2 mRNA. This co-localization is most apparent in the posteroventral part of the MEA, where 70% of ENKergic cells expressed VGLUT2. In addition, ppENK also co-localized with VGLUT1 because more than 95% of ENK cells in the basolateral amygdala expressed VGLUT1. In contrast, less than 25% of ENKergic cells expressed VGLUT1 in the lateral nucleus of the amygdale, with the majority of ENK cells expressing GAD65 mRNA in this nucleus. These results have broad implications for understanding the functional roles of enkephalinergic neurotransmission in the amygdaloid complex. J. Comp. Neurol. 506: 943-959, 2008.

show abstract

Activity-dependent liberation of synaptic neuropeptide vesicles

Cited by 110 publications

References 37 publications

Synaptic neuropeptide release induced by octopamine without Ca ²⁺ entry into the nerve terminal

Synaptic neuropeptide release induced by octopamine without Ca ²⁺ entry into the nerve terminal

Signaling for Vesicle Mobilization and Synaptic Plasticity

Enkephalin co‐expression with classic neurotransmitters in the amygdaloid complex of the rat

Contact Info

Product

Resources

About

Activity-dependent liberation of synaptic neuropeptide vesicles

Cited by 110 publications

References 37 publications

Synaptic neuropeptide release induced by octopamine without Ca 2+ entry into the nerve terminal

Synaptic neuropeptide release induced by octopamine without Ca 2+ entry into the nerve terminal

Signaling for Vesicle Mobilization and Synaptic Plasticity

Enkephalin co‐expression with classic neurotransmitters in the amygdaloid complex of the rat

Contact Info

Product

Resources

About

Synaptic neuropeptide release induced by octopamine without Ca ²⁺ entry into the nerve terminal

Synaptic neuropeptide release induced by octopamine without Ca ²⁺ entry into the nerve terminal