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1.
突触囊泡在钙离子(Ca2+)触发下释放神经递质普遍存在着同步和异步两种形式.突触囊泡膜蛋白(synaptotagmin 2,Syt-2)已被证实是Calyx of Held突触囊泡同步释放的Ca2+传感蛋白,而相关的异步释放Ca2+传感蛋白还有待于探索.虽然锶离子(Sr2+)因其物理和化学性质都接近Ca2+,且能触发更多的囊泡异步释放成分而成为研究异步释放机制的常用工具,但有关Sr2+触发异步释放的机制存在着争议.本文在胞外以Sr2+替换Ca2+的条件下,通过对野生型(WT)和Syt-2敲除型(Z2B-/-)小鼠Calyx突触囊泡自发和诱发释放的电生理特性分析,发现Syt-2是介导Sr2+诱发的突触囊泡快速释放的传感蛋白,但不是介导Sr2+相关神经递质异步释放和自发释放的传感蛋白;而未知的触发囊泡异步释放的传感蛋白相比Syt-2对Sr2+具有更高的亲和力,同时也介导突触囊泡的自发释放.这一研究为探索并最终发现触发囊泡异步释放的未知传感蛋白提供了新的线索. 相似文献
2.
Yaroslav S. Ermolyuk Felicity G. Alder Christian Henneberger Dmitri A. Rusakov Dimitri M. Kullmann Kirill E. Volynski 《PLoS biology》2012,10(9)
The efficacy of action potential evoked neurotransmitter release varies widely even among synapses supplied by the same axon, and the number of release-ready vesicles at each synapse is a major determinant of this heterogeneity. Here we identify a second, equally important, mechanism for release heterogeneity at small hippocampal synapses, the inter-synaptic variation of the exocytosis probability of release-ready vesicles. Using concurrent measurements of vesicular pool sizes, vesicular exocytosis rates, and presynaptic Ca2+ dynamics, in the same small hippocampal boutons, we show that the average fusion probability of release-ready vesicles varies among synapses supplied by the same axon with the size of the spike-evoked Ca2+ concentration transient. We further show that synapses with a high vesicular release probability exhibit a lower Ca2+ cooperativity, arguing that this is a direct consequence of increased Ca2+ influx at the active zone. We conclude that variability of neurotransmitter release under basal conditions at small central synapses is accounted for not only by the number of release-ready vesicles, but also by their fusion probabilities, which are set independently of bouton size by variable spike-evoked presynaptic Ca2+ influx.
Author Summary
Synaptic transmission underlies information transfer among neurons in the brain. The probability that a synapse will release neurotransmitter in response to an action potential varies widely, even among synapses supplied by the same axon. The molecular mechanisms underlying this heterogeneity remain poorly understood. At the level of single synapses, release efficacy is determined largely by two factors: (i) the number of neurotransmitter-containing vesicles ready to be released, and (ii) by the fusion probabilities of these vesicles. By using novel imaging techniques at individual hippocampal presynaptic boutons in culture, we distinguish two independent sources of variability of release probability in small central synapses. First, we find differences in the number of releasable vesicles, and second, we find differences in the exocytosis probability of individual vesicles. To our knowledge, this is the first direct experimental demonstration that the fusion probability of release-ready vesicles is variable among synapses supplied by a single axon, and contributes roughly as much to the overall variability in release probability as does the number of release-ready vesicles. 相似文献3.
《Cell》1994,79(4):717-727
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 Ca2+-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 Ca2+-triggering of synchronous neurotransmitter release, but is not essential for asynchronous or Ca2+-independent release. We propose that synaptotagmin I is the major low affinity Ca2+ sensor mediating Ca2+ regulation of synchronous neurotransmitter release in hippocampal neurons. 相似文献
4.
RIM‐binding proteins recruit BK‐channels to presynaptic release sites adjacent to voltage‐gated Ca2+‐channels
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The active zone of presynaptic nerve terminals organizes the neurotransmitter release machinery, thereby enabling fast Ca2+‐triggered synaptic vesicle exocytosis. BK‐channels are Ca2+‐activated large‐conductance K+‐channels that require close proximity to Ca2+‐channels for activation and control Ca2+‐triggered neurotransmitter release by accelerating membrane repolarization during action potential firing. How BK‐channels are recruited to presynaptic Ca2+‐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 Ca2+‐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 Ca2+‐channels, synaptic vesicles, and the membrane fusion machinery, thereby enabling tight spatio‐temporal coupling of Ca2+‐influx to Ca2+‐triggered neurotransmitter release in a presynaptic terminal. 相似文献
5.
Cynthia F. Barber Ramon A. Jorquera Jan E. Melom J. Troy Littleton 《The Journal of cell biology》2009,187(2):295-310
Ca2+ influx into synaptic compartments during activity is a key mediator of neuronal plasticity. Although the role of presynaptic Ca2+ in triggering vesicle fusion though the Ca2+ sensor synaptotagmin 1 (Syt 1) is established, molecular mechanisms that underlie responses to postsynaptic Ca2+ 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 Ca2+–binding sites, as well as serine 284, an evolutionarily conserved substitution for a key Ca2+-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 Ca2+ sensor for presynaptic vesicle fusion. 相似文献
6.
We examined the effects of osthole and imperatorin, two active compounds of Cnidium monnieri (L.) Cusson, on the release of glutamate from rat hippocampal synaptosomes and investigated the possible mechanism. The results showed that osthole or imperatorin significantly facilitated 4-aminopridine (4-AP)-evoked glutamate release in a concentration-dependent manner. The facilitatory action of osthole or imperatorin was blocked by the vesicular transporter inhibitor bafilomycin A1, not by the glutamate transporter inhibitor l-transpyrrolidine-2,4-dicarboxylic acid (l-trans-PDC), indicating that the release facilitation by osthole or imperatorin results from a enhancement of vesicular exocytosis and not from an increase of Ca2+-independent efflux via glutamate transporter. Examination of the effect of osthole and imperatorin on cytosolic [Ca2+] revealed that the facilitation of glutamate release could be attributed to an increase in voltage-dependent Ca2+ influx. Consistent with this, ω-conotoxin MVIIC, a wide-spectrum blocker of the N- and P/Q-type Ca2+ channels, significantly suppressed the osthole or imperatorin-mediated facilitation of glutamate release, but intracellular Ca2+ release inhibitor dantrolene had no effect. Osthole or imperatorin did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization; thus, the facilitation of 4-AP-evoked Ca2+ influx and glutamate release produced by osthole or imperatorin was not due to it decreasing synaptosomal excitability. In addition, osthole or imperatorin-mediated inhibition of 4-AP-evoked release was prevented by protein kinase C (PKC) inhibitors. Furthermore, osthole or imperatorin increased 4-AP-induced phosphorylation of PKC. Together, these results suggest that osthole or imperatorin effects a facilitation of glutamate release from nerve terminals by positively modulating N-and P/Q-type Ca2+ channel activation through a signaling cascade involving PKC. 相似文献
7.
Cristina M. Velázquez‐Marrero Héctor G. Marrero José R. Lemos 《Journal of cellular physiology》2010,225(1):223-232
Release of neurotransmitter is activated by the influx of calcium. Inhibition of Ca2+ channels results in less calcium influx into the terminals and presumably a reduction in transmitter release. In the neurohypophysis (NH), Ca2+ channel kinetics, and the associated Ca2+ influx, is primarily controlled by membrane voltage and can be modulated, in a voltage‐dependent manner, by G‐protein subunits interacting with voltage‐gated calcium channels (VGCCs). In this series of experiments we test whether the κ‐ and µ‐opioid inhibition of Ca2+ currents in NH terminals is voltage‐dependent. Voltage‐dependent relief of G‐protein inhibition of VGCC can be achieved with either a depolarizing square pre‐pulse or by action potential waveforms. Both protocols were tested in the presence and absence of opioid agonists targeting the κ‐ and µ‐receptors in neurohypophysial terminals. The κ‐opioid VGCC inhibition is relieved by such pre‐pulses, suggesting that this receptor is involved in a voltage‐dependent membrane delimited pathway. In contrast, µ‐opioid inhibition of VGCC is not relieved by such pre‐pulses, indicating a voltage‐independent diffusible second‐messenger signaling pathway. Furthermore, relief of κ‐opioid inhibition during a physiologic action potential (AP) burst stimulation indicates the possibility of activity‐dependent modulation in vivo. Differences in the facilitation of Ca2+ channels due to specific G‐protein modulation during a burst of APs may contribute to the fine‐tuning of Ca2+‐dependent neuropeptide release in other CNS terminals, as well. J. Cell. Physiol. 225: 223–232, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
8.
《Neurochemistry international》2009,54(6-8):416-423
We examined the effects of osthole and imperatorin, two active compounds of Cnidium monnieri (L.) Cusson, on the release of glutamate from rat hippocampal synaptosomes and investigated the possible mechanism. The results showed that osthole or imperatorin significantly facilitated 4-aminopridine (4-AP)-evoked glutamate release in a concentration-dependent manner. The facilitatory action of osthole or imperatorin was blocked by the vesicular transporter inhibitor bafilomycin A1, not by the glutamate transporter inhibitor l-transpyrrolidine-2,4-dicarboxylic acid (l-trans-PDC), indicating that the release facilitation by osthole or imperatorin results from a enhancement of vesicular exocytosis and not from an increase of Ca2+-independent efflux via glutamate transporter. Examination of the effect of osthole and imperatorin on cytosolic [Ca2+] revealed that the facilitation of glutamate release could be attributed to an increase in voltage-dependent Ca2+ influx. Consistent with this, ω-conotoxin MVIIC, a wide-spectrum blocker of the N- and P/Q-type Ca2+ channels, significantly suppressed the osthole or imperatorin-mediated facilitation of glutamate release, but intracellular Ca2+ release inhibitor dantrolene had no effect. Osthole or imperatorin did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization; thus, the facilitation of 4-AP-evoked Ca2+ influx and glutamate release produced by osthole or imperatorin was not due to it decreasing synaptosomal excitability. In addition, osthole or imperatorin-mediated inhibition of 4-AP-evoked release was prevented by protein kinase C (PKC) inhibitors. Furthermore, osthole or imperatorin increased 4-AP-induced phosphorylation of PKC. Together, these results suggest that osthole or imperatorin effects a facilitation of glutamate release from nerve terminals by positively modulating N-and P/Q-type Ca2+ channel activation through a signaling cascade involving PKC. 相似文献
9.
Xiao-lei Zhang Sara R. Guariglia Jennifer L. McGlothan Kirstie H. Stansfield Patric K. Stanton Tomás R. Guilarte 《PloS one》2015,10(5)
Childhood lead (Pb2+) intoxication is a global public health problem and accounts for 0.6% of the global burden of disease associated with intellectual disabilities. Despite the recognition that childhood Pb2+ intoxication contributes significantly to intellectual disabilities, there is a fundamental lack of knowledge on presynaptic mechanisms by which Pb2+ disrupts synaptic function. In this study, using a well-characterized rodent model of developmental Pb2+ neurotoxicity, we show that Pb2+ exposure markedly inhibits presynaptic vesicular release in hippocampal Schaffer collateral-CA1 synapses in young adult rats. This effect was associated with ultrastructural changes which revealed a reduction in vesicle number in the readily releasable/docked vesicle pool, disperse vesicle clusters in the resting pool, and a reduced number of presynaptic terminals with multiple mitochondria with no change in presynaptic calcium influx. These studies provide fundamental knowledge on mechanisms by which Pb2+ produces profound inhibition of presynaptic vesicular release that contribute to deficits in synaptic plasticity and intellectual development. 相似文献
10.
Double C2-domain protein (Doc2) is a Ca2+-binding protein implicated in asynchronous and spontaneous neurotransmitter release. Here we demonstrate that each of its C2 domains senses Ca2+; moreover, the tethered tandem C2 domains display properties distinct from the isolated domains. We confirm that overexpression of a mutant form of Doc2β, in which two acidic Ca2+ ligands in the C2A domain and two in the C2B domain have been neutralized, results in markedly enhanced asynchronous release in synaptotagmin 1–knockout neurons. Unlike wild-type (wt) Doc2β, which translocates to the plasma membrane in response to increases in [Ca2+]i, the quadruple Ca2+-ligand mutant does not bind Ca2+ but is constitutively associated with the plasma membrane; this effect is due to substitution of Ca2+ ligands in the C2A domain. When overexpressed in wt neurons, Doc2β affects only asynchronous release; in contrast, Doc2β Ca2+-ligand mutants that constitutively localize to the plasma membrane enhance both the fast and slow components of synaptic transmission by increasing the readily releasable vesicle pool size; these mutants also increase the frequency of spontaneous release events. Thus, mutations in the C2A domain of Doc2β that were intended to disrupt Ca2+ binding result in an anomalous enhancement of constitutive membrane-binding activity and endow Doc2β with novel functional properties. 相似文献
11.
Synaptotagmin-7 (Syt7) plays direct or redundant Ca2+ sensor roles in multiple forms of vesicle exocytosis in synapses. Here, we show that Syt7 is a redundant Ca2+ sensor with Syt1/Doc2 to drive spontaneous glutamate release, which functions uniquely to activate the postsynaptic GluN2B-containing NMDARs that significantly contribute to mental illness. In mouse hippocampal neurons lacking Syt1/Doc2, Syt7 inactivation largely diminishes spontaneous release. Using 2 approaches, including measuring Ca2+ dose response and substituting extracellular Ca2+ with Sr2+, we detect that Syt7 directly triggers spontaneous release via its Ca2+ binding motif to activate GluN2B-NMDARs. Furthermore, modifying the localization of Syt7 in the active zone still allows Syt7 to drive spontaneous release, but the GluN2B-NMDAR activity is abolished. Finally, Syt7 SNPs identified in bipolar disorder patients destroy the function of Syt7 in spontaneous release in patient iPSC-derived and mouse hippocampal neurons. Therefore, Syt7 could contribute to neuropsychiatric disorders through driving spontaneous glutamate release.Synaptotagmin-7 (Syt7) variants are associated with susceptibility to bipolar disorder; this study shows that Syt7 acts as a calcium sensor to drive spontaneous glutamate release which uniquely activates postsynaptic GluN2B-containing glutamate receptors. Interestingly, this function of Syt7 is disrupted in bipolar disorder susceptibility variants. 相似文献
12.
Hernández A Segura-Chama P Albiñana E Hernández-Cruz A Hernández-Guijo JM 《Cellular and molecular neurobiology》2010,30(8):1209-1216
Modifications in Ca2+ influx may lead to profound changes in the cell activity associated with Ca2+-dependent processes, from muscle contraction and neurotransmitter release to calcium-mediated cell death. Therefore, calcium
entry into the cell requires fine regulation. In this context, understanding of the modulation of voltage-dependent Ca2+ channels seems to be critical. The modulatory process results in the enhancement or decrement of calcium influx that may
regulate the local and global cytosolic Ca2+ concentrations. Here, we summarize the well-established data on this matter described in isolated chromaffin cells by our
laboratory and others, and the new results we have obtained in a more physiological preparation: freshly isolated slices of
mouse adrenal medullae. 相似文献
13.
G-protein-mediated inhibition of Ca2+ current is ubiquitous in neurons, and in synaptic terminals it can lead to a reduction in transmitter release (presynaptic inhibition). This type of Ca2+ current inhibition can often be relieved by prepulse depolarization, so the disinhibition of Ca2+ current can combine with Ca2+-dependent mechanisms for activity-induced synaptic facilitation to amplify this form of short-term plasticity. We combine a mathematical model of a G-protein-regulated Ca2+ channel with a model of transmitter secretion to study the potential effects of G-protein-mediated Ca2+ channel inhibition and disinhibition on transmitter release and facilitation. We investigate several scenarios, with the goal of observing a range of behaviors that may occur in different synapses. We find that the effects of Ca2+ channel disinhibition depend greatly on the location and distribution of inhibited channels. Facilitation can be greatly enhanced if all channels are subject to inhibition or if the subpopulation of channels subject to inhibition are located closer to release sites than those insensitive to inhibition, an arrangement that has been suggested by recent experiments (Stanley and Mirotznik, 1997). We also find that the effect of disinhibition on facilitation is greater for longer action potentials. Finally, in the case of homosynaptic inhibition, where Ca2+ channel inhibition occurs through the binding of transmitter molecules to presynaptic autoreceptors, there will be little reduction in transmitter release during the first of two successive bursts of impulses. The reduction of release during the second burst will be significantly greater, and if the unbinding rate of autoreceptors is relatively low, then the effects of G-protein-mediated channel inhibition become more pronounced as the duration of the interburst interval is increased up to a critical point, beyond which the inhibitory effects become less pronounced. This is in contrast to presynaptic depression due to the depletion of the releasable vesicle pool, where longer interburst intervals allow for a more complete replenishment of the pool. Thus, G-protein-mediated Ca2+ current inhibition leads to a reduction in transmitter release, while having a highly variable amplifying effect on synaptic facilitation. The dynamic properties of this form of presynaptic inhibition are very different from those of vesicle depletion. 相似文献
14.
How to make a synaptic ribbon: RIBEYE deletion abolishes ribbons in retinal synapses and disrupts neurotransmitter release
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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 Ca2+‐buffer EGTA, suggesting that synaptic ribbons mediate nano‐domain coupling of Ca2+ 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 Ca2+ channels. 相似文献
15.
《Cell calcium》2007,41(5-6):423-439
Katz and co-workers showed that Ca2+ triggers exocytosis. The existence of sub-micrometer domains of greater than 100 μM [Ca2+]i was postulated on theoretical grounds. Using a modified, low-affinity aequorin, Llinas et al. were the first to demonstrate the existence of Ca2+ ‘microdomains’ in squid presynaptic terminals. Over the past several years, it has become clear that individual Ca2+ nano- and microdomains forming around the mouth of voltage-gated Ca2+ channels ascertain the tight coupling of fast synaptic vesicle release to membrane depolarization by action potentials. Recent work has established different geometric arrangements of vesicles and Ca2+ channels at different central synapses and pointed out the role of Ca2+ syntillas – localized, store operated Ca2+ signals – in facilitation and spontaneous release. The coupling between Ca2+ increase and evoked exocytosis is more sluggish in peripheral terminals and neuroendocrine cells, where channels are less clustered and Ca2+ comes from different sources, including Ca2+ influx via the plasma membrane and the mobilization of Ca2+ from intracellular stores. Finally, also non- (electrically) excitable cells display highly localized Ca2+ signaling domains. We discuss in particular the organization of structural microdomains of Bergmann glia, specialized astrocytes of the cerebellum that have only recently been considered as secretory cells. Glial microdomains are the spatial substrate for functionally segregated Ca2+ signals upon metabotropic activation. Our review emphasizes the large diversity of different geometric arrangements of vesicles and Ca2+ sources, leading to a wide spectrum of Ca2+ signals triggering release. 相似文献
16.
Gilmanov IR Samigullin DV Vyskocil F Nikolsky EE Bukharaeva EA 《Journal of computational neuroscience》2008,25(2):296-307
The local calcium concentration in the active zone of secretion determines the number and kinetics of neurotransmitter quanta
released after the arrival of a nerve action potential in chemical synapses. The small size of mammalian neuromuscular junctions
does not allow direct measurement of the correlation between calcium influx, the state of endogenous calcium buffers determining
the local concentration of calcium and the time course of quanta exocytosis. In this work, we used computer modeling of quanta
release kinetics with various levels of calcium influx and in the presence of endogenous calcium buffers with varying mobilities.
The results of this modeling revealed the desynchronization of quanta release under low calcium influx in the presence of
an endogenous fixed calcium buffer, with a diffusion coefficient much smaller than that of free Ca2+, and synchronization occurred upon adding a mobile buffer. This corresponds to changes in secretion time course parameters
found experimentally (Samigullin et al., Physiol Res 54:129–132, 2005; Bukharaeva et al., J Neurochem 100:939–949, 2007). 相似文献
17.
Central synapses operate neurotransmission in several modes: synchronous/fast neurotransmission (neurotransmitters release is tightly coupled to action potentials and fast), asynchronous neurotransmission (neurotransmitter release is slower and longer lasting), and spontaneous neurotransmission (where small amounts of neurotransmitter are released without being evoked by an action potential). A substantial body of evidence from the past two decades suggests that seemingly identical synaptic vesicles possess distinct propensities to fuse, thus selectively serving different modes of neurotransmission. In efforts to better understand the mechanism(s) underlying the different modes of synaptic transmission, many research groups found that synaptic vesicles used in different modes of neurotransmission differ by a number of synaptic proteins. Synchronous transmission with higher temporal fidelity to stimulation seems to require synaptotagmin 1 and complexin for its Ca2+ sensitivity, RIM proteins for closer location of synaptic vesicles (SV) to the voltage operated calcium channels (VGCC), and dynamin for SV retrieval. Asynchronous release does not seem to require functional synaptotagmin 1 as a calcium sensor or complexins, but the activity of dynamin is indispensible for its maintenance. On the other hand, the control of spontaneous neurotransmission remains less clear as deleting a number of essential synaptic proteins does not abolish this type of synaptic vesicle fusion. VGCC distance from the SV seems to have little control on spontaneous transmission, while there is an involvement of functional synaptic proteins including synaptotagmins and complexin. Recently, presynaptic deficits have been proposed to contribute to a number of pathological conditions including cognitive and mental disorders. In this review, we evaluate recent advances in understanding the regulatory mechanisms of synaptic vesicle dynamics and in understanding how different molecular substrates maintain selective modes of neurotransmission. We also highlight the implications of these studies in understanding pathological conditions. 相似文献
18.
P. D. Bregestovski L. G. Khaspekov 《Biochemistry (Moscow) Supplemental Series A: Membrane and Cell Biology》2007,1(1):28-37
Calcium (Ca2+) is a second messenger regulating a wide variety of intracellular processes. Using GABA-and glycinergic synapses as examples, this review analyzes two functions of this unique ion: postsynaptic Ca2+-dependent modulation of receptor-operated channels and Ca2+-induced retrograde regulation of neurotransmitter release from the presynaptic terminals. Phosphorylation, rapid Ca2+-induced modulation via intermediate Ca2+-binding proteins, and changes in the number of functional receptors represent the main pathways of short-and long-term plasticity of postsynaptic receptor-operated channel machinery. Retrograde signaling is an example of synaptic modulation triggered by stimulation of postsynaptic cells and mediated via regulation of presynaptic neurotransmitter release. This mechanism provides postsynaptic neurons with efficient tools to control the presynaptic afferents in an activity-dependent mode. Elevation of intracellular Ca2+ in a postsynaptic neuron triggers the synthesis of endocannabinoids (derivatives of arachidonic acid). Their retrograde diffusion through the synaptic cleft and consequent activation of presynaptic G-protein coupled to CB1 receptors inhibits the release of neurotransmitter. These mechanisms of double modulation, which include control over the function of postsynaptic ion channels and retrograde suppression of the release machinery, play an important role in Ca2+-dependent control of the main excitatory and inhibitory synaptic pathways in the mammalian nervous system. 相似文献
19.
Grinnell Alan D. Chen Bo-Ming Kashani Amir Lin Jennifer Suzuki Kazuhiro Kidokoro Yoshiaki 《Brain Cell Biology》2003,32(5-8):489-503
Integrins are found at most or all synapses and play a variety of roles. At frog neuromuscular junctions, mechanical tension on integrins due to muscle stretch or hypertonicity causes a powerful modulation of release efficacy. Understanding the mechanism(s) of integrin-mediated modulation will likely further our understanding of mechanisms of neurotransmitter release. The modulation of evoked release with stretch occurs with no detectable delay, does not adapt, and bypasses the Ca2+ triggering step in vesicle fusion. It depends primarily on integrin bonds to native ligands and requires that one or more proteins in the link between integrins and vesicle fusion be dephosphorylated. Hypertonicity, studied in both frog and Drosophila terminals, causes a larger but slower phasic-tonic change in spontaneous release, which is also Ca2+-independent and mostly dependent on integrins, but not dependent on the phosphorylation state of molecules in its pathway of action. In Drosophila, the integrin-dependent component involves the cAMP/PKA pathway, and is absent in mutants lacking PKA. Both stretch and hypertonicity responses in frog terminals are enhanced by agents that elevate PKA levels, suggesting that, in frogs, the cAMP/PKA cascade primarily determines the size of the pool of vesicles available for release by the integrin-mediated mechanism and is not a direct intermediary in the modulation. Evoked release is affected little or even inhibited by hypertonicity. In Drosophila, the inhibition can be explained by a decrease in Ca2+ influx. The effect of hypertonicity on evoked release in frogs may similarly be a balance between mechanisms that enhance spontaneous release and those that suppress I Ca. 相似文献
20.
《Cell calcium》2020
Synaptic transmission relies on rapid calcium (Ca2+) influx into presynaptic terminal via voltage-gated Ca2+ channels. However, smooth ER is present in presynaptic terminals and accumulating evidence indicate that ER Ca2+ signaling may play a modulatory role in synaptic transmission. Most recent publication by Lindhout and colleagues (EMBO J, 38 (2019) e101345) suggested that the fragmentation state of the ER affects synaptic vesicle release. Here we discuss these results as well as several key publications that addressed a connection between ER Ca2+ signaling and synaptic transmission. 相似文献