PP2 inhibits glutamate release from nerve endings by affecting vesicle mobilization
aSchool of Medicine, Fu Jen Catholic University, Hsin-Chuang, Taipei Hsien, Taiwan.Neuroreport (Impact Factor: 1.52). 12/2005; 16(17):1969-72. DOI: 10.1097/01.wnr.0000189758.57164.85
Src kinase is widely expressed in the brain and its inhibition with PP2 has previously been shown to depress depolarization-evoked glutamate release from rat cerebrocortical synaptosomes by reducing voltage-dependent Ca2+ entry. In this study, we further showed that the inhibitory effect of PP2 on 4-aminopyridine-evoked glutamate release results from a reduction of vesicular exocytosis and not from an inhibition of non-vesicular release. In addition, PP2 significantly inhibited ionomycin-induced or hypertonic sucrose-induced glutamate release. Also, disruption of cytoskeleton organization with cytochalasin D occluded the inhibitory action of PP2 on 4-aminopyridine and ionomycin-evoked glutamate release. These results suggest that PP2-mediated inhibition of glutamate release involves the modulation of some exocytotic steps, possibly through a regulation of actin cytoskeleton dynamics.
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- "High-frequency synaptic stimulation, epileptiform activity and spatial learning trials activate Src kinases and promote their association with presynaptic proteins, including synapsin I (Lauri et al., 2000; Sanna et al., 2000; Zhao et al., 2000). Studies using specific Src inhibitors indicate that Src-family kinases directly modulate neurotransmitter release by interfering with activity-dependent Ca 2+ entry, actin dynamics and exocytosis (Ohnishi et al., 2001; Baldwin et al., 2006; Cheng et al., 2007), however see (Wang, 2003; Shyu et al., 2005). One of the mechanisms suggested for Src regulation of neurotransmitter release is by modifying, through phosphorylation, the activity of proteins, such as the synapsins, involved in the regulation of exocytosis and synaptic vesicles trafficking (Messa et al., 2010; Bykhovskaia, 2011). "
ABSTRACT: Neuronal M-type K(+) channels heteromers of KCNQ2 and KCNQ3 subunits found in cell bodies, dendrites and the axon initial segment, regulate firing properties of neurons, while presynaptic KCNQ2 homomeric channels directly regulate neurotransmitter release. Previously, we have described a mechanism for gating down-regulation of KCNQ2 homomeric channels by calmodulin and syntaxin1A. Here, we describe a novel mechanism for KCNQ2 channels gating regulation utilized by Src, a non-receptor tyrosine kinase, in which two concurrent distinct structural rearrangements of the cytosolic termini induce two opposing effects, up-regulation of single-channel open probability, mediated by an N-terminal tyrosine, and reduction in functional channels, mediated by a C-terminal tyrosine. In contrast, Src regulation of KCNQ3 homomeric channels, shown before to be mediated by corresponding tyrosines, involves N-terminal tyrosine-mediated down-regulation of the open probability, rather than up-regulation. We argue that the dual bidirectional regulation of KCNQ2 functionality by Src, mediated via two separate sites, renders it modifiable by cellular factors that may specifically interact with either one of the sites, bearing potential significance in the fine-tuning of neurotransmitters release at nerve terminals. © 2015. Published by The Company of Biologists Ltd.Journal of Cell Science 08/2015; DOI:10.1242/jcs.173922 · 5.43 Impact Factor
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- "In others, however, TKs induced no change   or inhibited the Ca 2+ -induced exocytoses  . Finally, at brain glutamatergic synapses one laboratory reported a TKdependent reinforcement while another reported an inhibition  . Many of the above conclusions were not based on direct results but extrapolated from the effects of TK blockers, most often the large spectrum isoflavone genistein (GNS), used alone or in parallel with other drugs [1,2,4–6,8,9]. "
ABSTRACT: Studies carried out by immunofluorescence, patch-clamping and FM dye fluorescence consistently showed that the Ca(2+)-induced exocytosis of enlargeosomes, specific vesicles expressed by many cell types, is strongly reinforced by pre-treatment of the cells with genistein, a wide spectrum blocker of tyrosine kinases, which also induces many additional effects. Various other blockers of tyrosine kinases, however, were ineffective, and the same occurred with drugs mimicking most of the rapid, non-tyrosine kinase-dependent effects of genistein. The reinforcement of enlargeosome-regulated exocytosis, therefore, is a new effect of genistein and a peculiar property of the enlargeosome exocytosis, not shared by analogous processes.FEBS Letters 11/2007; 581(25):4932-6. DOI:10.1016/j.febslet.2007.09.026 · 3.17 Impact Factor
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ABSTRACT: Synapsins are synaptic vesicle-associated phosphoproteins implicated in the regulation of neurotransmitter release. Synapsin I is the major binding protein for the SH3 domain of the kinase c-Src in synaptic vesicles. Its binding leads to stimulation of synaptic vesicle-associated c-Src activity. We investigated the mechanism and role of Src activation by synapsins on synaptic vesicles. We found that synapsin is tyrosine phosphorylated by c-Src in vitro and on intact synaptic vesicles independently of its phosphorylation state on serine. Mass spectrometry revealed a single major phosphorylation site at Tyr(301), which is highly conserved in all synapsin isoforms and orthologues. Synapsin tyrosine phosphorylation triggered its binding to the SH2 domains of Src or Fyn. However, synapsin selectively activated and was phosphorylated by Src, consistent with the specific enrichment of c-Src in synaptic vesicles over Fyn or n-Src. The activity of Src on synaptic vesicles was controlled by the amount of vesicle-associated synapsin, which is in turn dependent on synapsin serine phosphorylation. Synaptic vesicles depleted of synapsin in vitro or derived from synapsin null mice exhibited greatly reduced Src activity and tyrosine phosphorylation of other synaptic vesicle proteins. Disruption of the Src-synapsin interaction by internalization of either the Src SH3 or SH2 domains into synaptosomes decreased synapsin tyrosine phosphorylation and concomitantly increased neurotransmitter release in response to Ca(2+)-ionophores. We conclude that synapsin is an endogenous substrate and activator of synaptic vesicle-associated c-Src and that regulation of Src activity on synaptic vesicles participates in the regulation of neurotransmitter release by synapsin.Journal of Biological Chemistry 06/2007; 282(21):15754-67. DOI:10.1074/jbc.M701051200 · 4.57 Impact Factor
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