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1.
Presynaptic terminals possess interlocking molecular mechanisms that control exocytosis. An example of such complexity is the modulation of release by presynaptic G Protein Coupled Receptors (GPCRs). GPCR ubiquity at synapses—GPCRs are present at every studied presynaptic terminal—underlies their critical importance in synaptic function. GPCRs mediate presynaptic modulation by mechanisms including via classical Gα effectors, but membrane-delimited actions of Gβγ can also alter probability of release by altering presynaptic ionic conductances. This directly or indirectly modifies action potential-evoked presynaptic Ca2+ entry. In addition, Gβγ can interact directly with SNARE complexes responsible for synaptic vesicle fusion to reduce peak cleft neurotransmitter concentrations during evoked release. The interaction of Gβγ with SNARE is displaced via competitive interaction with C2AB-domain containing calcium sensors such as synaptotagmin I in a Ca2+-sensitive manner, restoring exocytosis. Synaptic modulation of this form allows selective inhibition of postsynaptic receptor-mediated responses, and this, in combination with Ca2+ sensitivity of Gβγ effects on SNARE complexes allows for specific behavioral outcomes. One such outcome mediated by 5-HT receptors in the spinal cord seen in all vertebrates shows remarkable synergy between presynaptic effects of Gβγ and postsynaptic 5-HT-mediated changes in activation of Ca2+-dependent K+ channels. While acting through entirely separate cellular compartments and signal transduction pathways, these effects converge on the same effect on locomotion and other critical functions of the central nervous system. 相似文献
2.
The active zone of presynaptic nerve terminals organizes the neurotransmitter release machinery, thereby enabling fast Ca 2+‐triggered synaptic vesicle exocytosis. BK‐channels are Ca 2+‐activated large‐conductance K +‐channels that require close proximity to Ca 2+‐channels for activation and control Ca 2+‐triggered neurotransmitter release by accelerating membrane repolarization during action potential firing. How BK‐channels are recruited to presynaptic Ca 2+‐channels, however, is unknown. Here, we show that RBPs (for RIM‐binding proteins), which are evolutionarily conserved active zone proteins containing SH3‐ and FN3‐domains, directly bind to BK‐channels. We find that RBPs interact with RIMs and Ca 2+‐channels via their SH3‐domains, but to BK‐channels via their FN3‐domains. Deletion of RBPs in calyx of Held synapses decreased and decelerated presynaptic BK‐currents and depleted BK‐channels from active zones. Our data suggest that RBPs recruit BK‐channels into a RIM‐based macromolecular active zone complex that includes Ca 2+‐channels, synaptic vesicles, and the membrane fusion machinery, thereby enabling tight spatio‐temporal coupling of Ca 2+‐influx to Ca 2+‐triggered neurotransmitter release in a presynaptic terminal. 相似文献
3.
Ca 2+/calmodulin-dependent protein kinase II (CaMKII) and the BK channel are enriched at the presynaptic nerve terminal, where
CaMKII associates with synaptic vesicles whereas the BK channel colocalizes with voltage-sensitive Ca 2+ channels in the plasma membrane. Mounting evidence suggests that these two proteins play important roles in controlling neurotransmitter
release. Presynaptic BK channels primarily serve as a negative regulator of neurotransmitter release. In contrast, presynaptic
CaMKII either enhances or inhibits neurotransmitter release and synaptic plasticity depending on experimental or physiological
conditions and properties of specific synapses. The different functions of presynaptic CaMKII appear to be mediated by distinct
downstream proteins, including the BK channel. 相似文献
4.
Ca 2+ influx into synaptic compartments during activity is a key mediator of neuronal plasticity. Although the role of presynaptic Ca 2+ in triggering vesicle fusion though the Ca 2+ sensor synaptotagmin 1 (Syt 1) is established, molecular mechanisms that underlie responses to postsynaptic Ca 2+ influx remain unclear. In this study, we demonstrate that fusion-competent Syt 4 vesicles localize postsynaptically at both neuromuscular junctions (NMJs) and central nervous system synapses in Drosophila melanogaster. Syt 4 messenger RNA and protein expression are strongly regulated by neuronal activity, whereas altered levels of postsynaptic Syt 4 modify synaptic growth and presynaptic release properties. Syt 4 is required for known forms of activity-dependent structural plasticity at NMJs. Synaptic proliferation and retrograde signaling mediated by Syt 4 requires functional C2A and C2B Ca 2+–binding sites, as well as serine 284, an evolutionarily conserved substitution for a key Ca 2+-binding aspartic acid found in other synaptotagmins. These data suggest that Syt 4 regulates activity-dependent release of postsynaptic retrograde signals that promote synaptic plasticity, similar to the role of Syt 1 as a Ca 2+ sensor for presynaptic vesicle fusion. 相似文献
5.
Presynaptic group III metabotropic glutamate receptors (mGluRs) and Ca 2+ channels are the main neuronal activity-dependent regulators of synaptic vesicle release, and they use common molecules in their signaling cascades. Among these, calmodulin (CaM) and the related EF-hand Ca 2+-binding proteins are of particular importance as sensors of presynaptic Ca 2+, and a multiple of them are indeed utilized in the signaling of Ca 2+ channels. However, despite its conserved structure, CaM is the only known EF-hand Ca 2+-binding protein for signaling by presynaptic group III mGluRs. Because the mGluRs and Ca 2+ channels reciprocally regulate each other and functionally converge on the regulation of synaptic vesicle release, the mGluRs would be expected to utilize more EF-hand Ca 2+-binding proteins in their signaling. Here I show that calcium-binding protein 1 (CaBP1) bound to presynaptic group III mGluRs competitively with CaM in a Ca 2+-dependent manner and that this binding was blocked by protein kinase C (PKC)-mediated phosphorylation of these receptors. As previously shown for CaM, these results indicate the importance of CaBP1 in signal cross talk at presynaptic group III mGluRs, which includes many molecules such as cAMP, Ca 2+, PKC, G protein, and Munc18-1. However, because the functional diversity of EF-hand calcium-binding proteins is extraordinary, as exemplified by the regulation of Ca 2+ channels, CaBP1 would provide a distinct way by which presynaptic group III mGluRs fine-tune synaptic transmission. 相似文献
6.
Mice carrying a mutation in the synaptotagmin I gene were generated by homologous recombination. Mutant mice are phenotypically normal as heterozygotes, but die within 48 hr after birth as homozygotes. Studies of hippocampal neurons cultured from homozygous mutant mice reveal that synaptic transmission is severely impaired. The synchronous, fast component of Ca 2+-dependent neurotransmitter release is decreased, whereas asynchronous release processes, including spontaneous synaptic activity (miniature excitatory postsynaptic current frequency) and release triggered by hypertonic solution or α-latrotoxin, are unaffected. Our findings demonstrate that synaptotagmin I function is required for Ca 2+-triggering of synchronous neurotransmitter release, but is not essential for asynchronous or Ca 2+-independent release. We propose that synaptotagmin I is the major low affinity Ca 2+ sensor mediating Ca 2+ regulation of synchronous neurotransmitter release in hippocampal neurons. 相似文献
7.
We discuss a biophysical model of synaptic plasticity that provides a unified view of the outcomes of synaptic modification protocols, including: (1) prescribed time courses of postsynaptic intracellular Ca 2+ release, (2) postsynaptic voltage clamping with presentation of presynaptic spike trains at various frequencies, (3) direct postsynaptic response to presynaptic spike trains at various frequencies, and (4) LTP/LTD as a response to precisely timed presynaptic and postsynaptic spikes. 相似文献
8.
Axonal ionotropic receptors are present in a variety of neuronal types, and their function has largely been associated with the modulation of axonal activity and synaptic release. It is usually assumed that activation of axonal GABA ARs comes from spillover, but in cerebellar molecular layer interneurons (MLIs) the GABA source is different: in these cells, GABA release activates presynaptic GABA A autoreceptors (autoRs) together with postsynaptic targets, producing an autoR-mediated synaptic event. The frequency of presynaptic, autoR-mediated miniature currents is twice that of their somatodendritic counterparts, suggesting that autoR-mediated responses have an important effect on interneuron activity. Here, we used local Ca 2+ photolysis in MLI axons of juvenile rats to evoke GABA release from individual varicosities to study the activation of axonal autoRs in single release sites. Our data show that single-site autoR conductances are similar to postsynaptic dendritic conductances. In conditions of high [Cl −] i, autoR-mediated conductances range from 1 to 5 nS; this corresponds to ∼30–150 GABA A channels per presynaptic varicosity, a value close to the number of channels in postsynaptic densities. Voltage responses produced by the activation of autoRs in single varicosities are amplified by a Na v-dependent mechanism and propagate along the axon with a length constant of 91 µm. Immunolabeling determination of synapse location shows that on average, one third of the synapses produce autoR-mediated signals that are large enough to reach the axon initial segment. Finally, we show that single-site activation of presynaptic GABA A autoRs leads to an increase in MLI excitability and thus conveys a strong feedback signal that contributes to spiking activity. 相似文献
9.
Dopamine and glutamate systems are both involved in cognitive, behavioral, and motor processes. Dysfunction of dopamine–glutamate interplay has been suggested in several psychotic diseases, above all in schizophrenia, for which there exists a need for novel medications. Intracellular calcium-dependent transduction pathways are key determinants of dopamine–glutamate interactions, which take place mainly, albeit not exclusively, in the postsynaptic density (PSD), a highly specialized postsynaptic ultrastructure. Stimulation of dopamine and glutamate receptors modulates the gene expression and the function of specific PSD proteins, the “scaffolding” proteins (Homer, Shank, and PSD95), belonging to a complex Ca 2+-regulated network that integrates and converges dopamine and glutamate signaling to appropriate nuclear targets. Dysfunction of scaffolding proteins leads to severe impairment of Ca 2+-dependent signaling, which may underlie the dopamine–glutamate aberrations putatively implicated in the pathogenesis of psychotic disorders. Antipsychotic therapy has been demonstrated to directly and indirectly affect the neuronal Ca 2+-dependent pathways through the modulation of PSD scaffolding proteins, such as Homer, therefore influencing both dopaminergic and glutamatergic functions and enforcing Ca 2+-mediated long-term synaptic changes. In this review, we will discuss the role of PSD scaffolding proteins in routing Ca 2+-dependent signals to the nucleus. In particular, we will address the implication of PSD scaffolding proteins in the intracellular connections between dopamine and glutamate pathways, which involve both Ca 2+-dependent and Ca 2+-independent mechanisms. Finally, we will discuss how new strategies for the treatment of psychosis aim at developing antipsychotics that may impact both glutamate and dopamine signaling, and what should be the possible role of PSD scaffolding proteins. 相似文献
10.
Communication between neuronal and glial cells is important for many brain functions. Astrocytes can modulate synaptic strength via Ca 2+-stimulated release of various gliotransmitters, including glutamate and ATP. A physiological role of ATP release from astrocytes was suggested by its contribution to glial Ca 2+-waves and purinergic modulation of neuronal activity and sleep homeostasis. The mechanisms underlying release of gliotransmitters remain uncertain, and exocytosis is the most intriguing and debated pathway. We investigated release of ATP from acutely dissociated cortical astrocytes using “sniff-cell” approach and demonstrated that release is vesicular in nature and can be triggered by elevation of intracellular Ca 2+ via metabotropic and ionotropic receptors or direct UV-uncaging. The exocytosis of ATP from neocortical astrocytes occurred in the millisecond time scale contrasting with much slower nonvesicular release of gliotransmitters via Best1 and TREK-1 channels, reported recently in hippocampus. Furthermore, we discovered that elevation of cytosolic Ca 2+ in cortical astrocytes triggered the release of ATP that directly activated quantal purinergic currents in the pyramidal neurons. The glia-driven burst of purinergic currents in neurons was followed by significant attenuation of both synaptic and tonic inhibition. The Ca 2+-entry through the neuronal P2X purinoreceptors led to phosphorylation-dependent down-regulation of GABAA receptors. The negative purinergic modulation of postsynaptic GABA receptors was accompanied by small presynaptic enhancement of GABA release. Glia-driven purinergic modulation of inhibitory transmission was not observed in neurons when astrocytes expressed dn-SNARE to impair exocytosis. The astrocyte-driven purinergic currents and glia-driven modulation of GABA receptors were significantly reduced in the P2X4 KO mice. Our data provide a key evidence to support the physiological importance of exocytosis of ATP from astrocytes in the neocortex. 相似文献
11.
Synaptic ribbons are large proteinaceous scaffolds at the active zone of ribbon synapses that are specialized for rapid sustained synaptic vesicles exocytosis. A single ribbon‐specific protein is known, RIBEYE, suggesting that ribbons may be constructed from RIBEYE protein. RIBEYE knockdown in zebrafish, however, only reduced but did not eliminate ribbons, indicating a more ancillary role. Here, we show in mice that full deletion of RIBEYE abolishes all presynaptic ribbons in retina synapses. Using paired recordings in acute retina slices, we demonstrate that deletion of RIBEYE severely impaired fast and sustained neurotransmitter release at bipolar neuron/AII amacrine cell synapses and rendered spontaneous miniature release sensitive to the slow Ca 2+‐buffer EGTA, suggesting that synaptic ribbons mediate nano‐domain coupling of Ca 2+ channels to synaptic vesicle exocytosis. Our results show that RIBEYE is essential for synaptic ribbons as such, and may organize presynaptic nano‐domains that position release‐ready synaptic vesicles adjacent to Ca 2+ channels. 相似文献
12.
Postsynaptic Ca2+ signal influences synaptic transmission through multiple mechanisms. Some of them involve retrograde messengers that are released from postsynaptic neurons in a Ca2+-dependent manner and modulate transmitter release through activation of presynaptic receptors. Recent studies have revealed essential roles of endocannabinoids in retrograde modulation of synaptic transmission. Endocannabinoid release is induced by either postsynaptic Ca2+ elevation alone or activation of postsynaptic Gq/11-coupled receptors with or without Ca2+ elevation. The former pathway is independent of phospholipase Cbeta (PLCbeta) and requires a large Ca2+ elevation to a micromolar range. The latter pathway requires PLCbeta and is facilitated by a moderate Ca2+ elevation to a submicromolar range. This facilitation is caused by Ca2+-dependency of receptor-driven PLCbeta activation. The released endocannabinoids then activate presynaptic cannabinoid receptor type 1 (CB1), and suppress transmitter release from presynaptic terminals. Both CB1 receptors and Gq/11-coupled receptors are widely distributed in the brain. Thus, the endocannabinoid-mediated retrograde modulation may be an important and widespread mechanism in the brain, by which postsynaptic events including Gq/11-coupled receptor activation and Ca2+ elevation can retrogradely influence presynaptic function. 相似文献
13.
Elevation of cytosolic Ca 2+ level in the postsynaptic cell is critical for the induction of many forms of activity-dependent synaptic modulation. Based on our recent evidence that in muscle cells and fibroblasts constitutive exocytosis is increased by elevating cytosolic Ca 2+ levels, we hypothesize that Ca 2+ -dependent exocytosis at the postsynaptic site may provide a mechanism for a localized, activitt-dependent synaptic modulation. 1994 John Wiley & Sons, Inc. 相似文献
14.
Glutamatergic transmission in the central nervous system (CNS) is mediated by ionotropic, ligand-gated receptors (iGluRs), and metabotropic receptors (mGluRs). mGluRs are coupled to GTP-binding regulatory proteins (G-proteins) and modulate different second messenger pathways. Multiple effects have been described following their activation; among others, regulation of fast synaptic transmission, changes in synaptic plasticity, and modification of the threshold for seizure generation. Some of the major roles played by the activation of mGluRs might depend on the modulation of high-voltage-activated (HVA) calcium (Ca 2+) currents. Some HVA Ca 2+ channels (N-, P-, and Q-type channels) are signaling components at most presynaptic active zones. Their mGluR-mediated inhibition reduces synaptic transmission. The interference, by agonists at mGluRs, on L-type channels might affect the repetitive neuronal firing behavior and the integration of complex events at the somatic level. In addition, the mGluR-mediated effects on voltagegated Ca 2+ signals have been suggested to strongly influence neurotoxicity. Rather different coupling mechanisms underlie the relation between mGluRs and Ca 2+ currents: Together with a fast, membrane-delimited mechanism of action, much slower responses, involving intracellular second messengers, have also been postulated. In the recent past, the relative paucity of selective agonists and antagonists for the different subclasses of mGluRs had hampered the clear definition of the roles of mGluRs in brain function. However, the recent availability of new pharmacological tools is promising to provide a better understanding of the neuronal functions related to different mGluR subtypes. The analysis of the mGluR-mediated modulation of Ca 2+ conductances will probably offer new insights into the characterization of synaptic transmission and the development of neuroprotective agents. 相似文献
15.
Synaptic plasticity results from changes in the strength of synaptic transmission upon repetitive stimulation. The amount of neurotransmitter released from presynaptic terminals can regulate short-term plasticity that lasts for a few minutes. This review focuses on short-term plasticity of small synaptic vesicle (SSV) and large dense-core vesicle (LDCV) exocytosis. Whereas SSVs contain classical neurotransmitters and activate ion channels, LDCVs contain neuropeptides and hormones which primarily activate G protein-coupled receptors (GPCRs). Thus, LDCV exocytosis is mainly associated with modulation of synaptic activity and cannot induce synaptic activity by itself. As in SSV exocytosis, repetitive stimulation leads to short-term enhancement of LDCV exocytosis: i.e., activity-dependent potentiation (ADP) which represents potentiation of neurotransmitter release. Short-term plasticity of SSV exocytosis results from Ca 2+ accumulation, but ADP of LDCV exocytosis does not. Here, we review the signaling mechanisms and differences of short-term plasticity in exocytotic processes of SSV and LDCV. 相似文献
16.
Homeostatic synaptic plasticity is a negative-feedback mechanism for compensating excessive excitation or inhibition of neuronal activity. When neuronal activity is chronically suppressed, neurons increase synaptic strength across all affected synapses via synaptic scaling. One mechanism for this change is alteration of synaptic AMPA receptor (AMPAR) accumulation. Although decreased intracellular Ca 2+ levels caused by chronic inhibition of neuronal activity are believed to be an important trigger of synaptic scaling, the mechanism of Ca 2+-mediated AMPAR-dependent synaptic scaling is not yet understood. Here, we use dissociated mouse cortical neurons and employ Ca 2+ imaging, electrophysiological, cell biological, and biochemical approaches to describe a novel mechanism in which homeostasis of Ca 2+ signaling modulates activity deprivation-induced synaptic scaling by three steps: (1) suppression of neuronal activity decreases somatic Ca 2+ signals; (2) reduced activity of calcineurin, a Ca 2+-dependent serine/threonine phosphatase, increases synaptic expression of Ca 2+-permeable AMPARs (CPARs) by stabilizing GluA1 phosphorylation; and (3) Ca 2+ influx via CPARs restores CREB phosphorylation as a homeostatic response by Ca 2+-induced Ca 2+ release from the ER. Therefore, we suggest that synaptic scaling not only maintains neuronal stability by increasing postsynaptic strength but also maintains nuclear Ca 2+ signaling by synaptic expression of CPARs and ER Ca 2+ propagation. 相似文献
17.
The regulated release of neurotransmitter occurs via the fusion of synaptic vesicles (SVs) at specialized regions of the presynaptic membrane called active zones (AZs). These regions are defined by a cytoskeletal matrix assembled at AZs (CAZ), which functions to direct SVs toward docking and fusion sites and supports their maturation into the readily releasable pool. In addition, CAZ proteins localize voltage‐gated Ca 2+ channels at SV release sites, bringing the fusion machinery in close proximity to the calcium source. Proteins of the CAZ therefore ensure that vesicle fusion is temporally and spatially organized, allowing for the precise and reliable release of neurotransmitter. Importantly, AZs are highly dynamic structures, supporting presynaptic remodeling, changes in neurotransmitter release efficacy, and thus presynaptic forms of plasticity. In this review, we discuss recent advances in the study of active zones, highlighting how the CAZ molecularly defines sites of neurotransmitter release, endocytic zones, and the integrity of synapses. 相似文献
18.
The neurotransmitter glutamate increases cerebral blood flow by activating postsynaptic neurons and presynaptic glial cells within the neurovascular unit. Glutamate does so by causing an increase in intracellular Ca 2+ concentration ([Ca 2+] i) in the target cells, which activates the Ca 2+/Calmodulin-dependent nitric oxide (NO) synthase to release NO. It is unclear whether brain endothelial cells also sense glutamate through an elevation in [Ca 2+] i and NO production. The current study assessed whether and how glutamate drives Ca 2+-dependent NO release in bEND5 cells, an established model of brain endothelial cells. We found that glutamate induced a dose-dependent oscillatory increase in [Ca 2+] i, which was maximally activated at 200 μM and inhibited by α-methyl-4-carboxyphenylglycine, a selective blocker of Group 1 metabotropic glutamate receptors. Glutamate-induced intracellular Ca 2+ oscillations were triggered by rhythmic endogenous Ca 2+ mobilization and maintained over time by extracellular Ca 2+ entry. Pharmacological manipulation revealed that glutamate-induced endogenous Ca 2+ release was mediated by InsP 3-sensitive receptors and nicotinic acid adenine dinucleotide phosphate (NAADP) gated two-pore channel 1. Constitutive store-operated Ca 2+ entry mediated Ca 2+ entry during ongoing Ca 2+ oscillations. Finally, glutamate evoked a robust, although delayed increase in NO levels, which was blocked by pharmacologically inhibition of the accompanying intracellular Ca 2+ signals. Of note, glutamate induced Ca 2+-dependent NO release also in hCMEC/D3 cells, an established model of human brain microvascular endothelial cells. This investigation demonstrates for the first time that metabotropic glutamate-induced intracellular Ca 2+ oscillations and NO release have the potential to impact on neurovascular coupling in the brain. 相似文献
19.
Activation of phospholipase C (PLC)-linked signaling cascades in nonexcitable cells stimulates Ca 2+ release from inositol-1,4,5-trisphosphate (IP 3)-sensitive intracellular Ca 2+ stores and activation of Ca 2+ entry via plasma membrane Ca 2+ channels. The attention of investigators is currently focused on the properties and molecular basis of channels involved in Ca 2+ entry into nonexcitable cells. According to current views, mammalian TRP proteins are involved in receptor-and store-dependent influx of Ca 2+; however, little is known about the linkage between specific TRP proteins and endogenous channels responsible for Ca 2+ entry. The aim of the present study was to elucidate the role of TRPC3 in the formation of store-dependent or receptor-operated pathways of Ca 2+ entry into A431 cells. Registration of Ca 2+ influx based on fluorescence measurements of intracellular Ca 2+ concentrations and analysis of integral membrane currents revealed that partial inhibition of TRPC3 expression by small interfering RNA (siRNA) results in suppression of store-dependent Ca 2+ entry without any effect on receptor-operated Ca 2+ influx. In-depth studies of single channels revealed that TRPC3 suppression in A431 cells results in the disappearance of one type of store-operated channels and formation of a novel type of store-independent Ca 2+-permeable channels. This, in turn, testifies to the crucial role of TRPC3 in normal functioning of store-operated Ca 2+ channels in A431 cells. 相似文献
20.
Oxygen-glucose deprivation (OGD) leads to depression of evoked synaptic transmission, for which the mechanisms remain unclear. We hypothesized that increased presynaptic [Ca 2+] i during transient OGD contributes to the depression of evoked field excitatory postsynaptic potentials (fEPSPs). Additionally, we hypothesized that increased buffering of intracellular calcium would shorten electrophysiological recovery after transient ischemia. Mouse hippocampal slices were exposed to 2 to 8 min of OGD. fEPSPs evoked by Schaffer collateral stimulation were recorded in the stratum radiatum, and whole cell current or voltage clamp recordings were performed in CA1 neurons. Transient ischemia led to increased presynaptic [Ca 2+] i, (shown by calcium imaging), increased spontaneous miniature EPSP/Cs, and depressed evoked fEPSPs, partially mediated by adenosine. Buffering of intracellular Ca 2+ during OGD by membrane-permeant chelators (BAPTA-AM or EGTA-AM) partially prevented fEPSP depression and promoted faster electrophysiological recovery when the OGD challenge was stopped. The blocker of BK channels, charybdotoxin (ChTX), also prevented fEPSP depression, but did not accelerate post-ischemic recovery. These results suggest that OGD leads to elevated presynaptic [Ca 2+] i, which reduces evoked transmitter release; this effect can be reversed by increased intracellular Ca 2+ buffering which also speeds recovery. 相似文献
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