Calcium Entry and Action at the Presynaptic Nerve Terminal. Proceedings of a conference. Baltimore, Md, October 15-17, 1990 (original) (raw)
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Calcium and transmitter release
Journal of Physiology-Paris, 1993
The mechanism of transmitter release by intracellular Ca has been explored by recording presynaptic Ca concentration ([Ca2+]i) with Ca-sensitive fluorescent dyes and by controlling [Ca2+]i with photosensitive Ca chelators. [Ca2+]i decays slowly (in seconds) after presynaptic action potentials, while transmitter release lasts only a few ms after each spike at fast synapses. Simulations of Ca diffusing from Ca channels opened during action potentials suggest that transmitter is released by brief, localized [Ca2+]i reaching about 100 }aM ('Ca domains'). Several indirect measures of [Ca2÷]i levels achieved at release sites are in agreement with this estimate. Synaptic facilitation is a short-term synaptic plasticity in which transmitter release is enhanced for up to 1 s following prior activity. This seems to be due to the residual effect of Ca bound to a different site from the multiple fast, low-affinity binding sites that Ca must occupy to trigger secretion. The release of transmitter by localized Ca domains explains the variable degree of apparent cooperativity of Ca action obtained when relating transmitter release to Ca influx. Increasing Ca influx by elevating extracellular [Ca 2+] increases the [Ca2+]i in each Ca domain, and release increases with a high-power dependence on Ca influx because of a high degree of Ca cooperativity. However, prolonging presynaptic spikes or using depolarizing pulses of increasing amplitude increases Ca influx by opening more Ca channels and increasing the number of Ca domains locally triggering release. Partial overlap of these domains results in a slightly greater than linear dependence of release on total Ca influx. Post-tetanic potentiation (PTP) is a minute-long form of synaptic plasticity that correlates with measures of residual presynaptic [Ca2+]i. The linear relationship between PTP and residual [Ca2+]i suggests that, as in synaptic facilitation, Ca seems to act at a different site from those that directly trigger release. Presynaptic sodium accumulation also contributes to PTP, apparently by reducing the Na gradient across the presynaptic membrane and impeding the removal of presynaptic Ca accumulated in the tetanus by Na/Ca exchange. Transmitter release at crayfish motor nerve terminals can be reduced by presynaptic inhibition, which reduces the Ca influx into terminals. Serotonin enhances transmitter release without increasing either resting [Ca2+]i or Ca influx during spikes, apparently operating at a site 'downstream' of Ca to modulate release. Spikes transiently accelerate transmitter release triggered by elevation of [Ca2+]i using photosensitive chelators, even in low-[Ca 2+] media that blocked detectable transmitter release. This was believed to show that the depolarization of an action potential can directly trigger phasic transmitter release when presynaptic [Ca2+]i is raised. However, measurements of presynaptic [Ca2+]i in these solutions showed that [Ca2+]i influx had not been fully blocked, and increasing the stimulus frequency revealed clear postsynaptic responses. When Ca influx was effectively blocked using external Ca chelators, action potentials were ineffective in triggering release, even when it was activated by photolytic release of Ca from presynaptically injected caged Ca chclators. Flash photolysis of the slowly binding photosensitive Ca chelator DM-nitrophen leads to an intense, brief presynaptic [Ca2+]i spike that triggers phasic transmitter release, producing a postsynaptic response resembling an EPSP. Secretion from chromaffin cells can be monitored as a membrane capacitance increase while raising [Ca2+]i with photosensitive chelators. Exposure to a conditioning, modest rise in [Ca2÷]i lasting 30 s increases the maximum rate of secretion triggered by a subsequent step rise in [Ca2+]i. Ca therefore not only triggers exocytosis, but seems to 'prime' the process, perhaps by mobilizing secretory granules to docking sites at the membrane. Large [Ca2+]i steps sometimes trigger a sudden reduction in membrane capacitance which may reflect a Ca-activated recovery of vesicular membrane by endocytosis. Slow synapses release transmitter from vesicles not clustered near the membrane, and not subject to the high [Ca2+]i levels in Ca domains.
Current opinion in neurobiology, 2003
In vertebrates, the physical coupling between presynaptic calcium channels and synaptic vesicle release proteins enhances the efficiency of neurotransmission. Recent evidence indicates that these synaptic proteins may feedback directly on synaptic release by negatively regulating calcium entry, and indirectly through pathways involving second messenger molecules. Studies of individual neurons from both vertebrates and invertebrates have provided novel insights into the roles of scaffolding proteins in calcium channel targeting and neurotransmitter release. These studies require us to expand current models of synaptic transmission. Abbreviations CASK calcium/calmodulin-dependent serine protein kinase CSP cysteine string protein Mint1 munc18-interacting protein PKC protein kinase C SCG superior cervical ganglion synprint synaptic protein interaction site Functional interactions between presynaptic calcium channels and the neurotransmitter release machinery Spafford and Zamponi 309 www.current-opinion.com Current Opinion in Neurobiology 2003, 13:308-314 42. Leveque C, Pupier S, Marqueze B, Geslin L, Kataoka M, Takahashi M, De Waard M, Seagar M: Interaction of cysteine string proteins with the alpha1A subunit of the P/Q-type calcium channel. Enhancement of presynaptic calcium current by cysteine string protein. J Physiol 2002, 538:383-389. 44. Blackmer T, Larsen EC, Takahashi M, Martin TF, Alford S, Hamm HE: G protein betagamma subunit-mediated presynaptic inhibition: regulation of exocytotic fusion downstream of Ca 2þ entry. Science 2001, 292:293-297. The authors present evidence that G proteins can regulate synaptic transmission directly and independently of the pathway through the inhibition of N-type calcium channels. This article is complementary to the work of Jarvis et al. [33]
Effects of membrane depolarization on intracellular calcium in single nerve terminals
Brain Research, 1990
The [Ca2+]i of individual neurosecretory nerve terminals loaded with the fluorescent probe fura-2 was monitored during depolarizing stimuli and in the presence of substances known to induce or block neurohormone release. Induction of membrane depolarization with elevated [K ÷] or veratridine led to a rapid increase in [Ca2+]i that was sensitive to block by substances which block voltage-sensitive L-type Ca 2÷ channels such as the dihydropyridine nicardipine and by D-888. Relaxin, cholecystokinin and enkephalin which have been reported to regulate vasopressin and oxytocin secretion at the nerve endings were without effect on basal [Ca2+]i or K+-stimulated increases in [CaZ+]i.
Neuroscience research, 2018
At the presynaptic terminal, neuronal firing activity induces membrane depolarization and subsequent Ca entry through voltage-gated Ca (Ca) channels triggers neurotransmitter release from the active zone. Presynaptic Ca channels form a large signaling complex, which targets synaptic vesicles to Ca channels for efficient release and mediates Ca channel regulation. The presynaptic Ca2 channel family (comprising Ca2.1, Ca2.2 and Ca2.3 isoforms) encode the pore-forming α1 subunit. The cytoplasmic regions are the target of regulatory proteins for channel modulation. Modulation of presynaptic Ca channels has a powerful influence on synaptic transmission. This article overviews spatial and temporal regulation of Ca channels by effectors and sensors of Ca signaling, and describes the emerging evidence for a critical role of Ca channel regulation in control of synaptic transmission and presynaptic plasticity. Sympathetic superior cervical ganglion neurons in culture expressing Ca2.2 channels...
Ca 2+ Dependent Regulation of Presynaptic Stimulus-Secretion Coupling
Journal of Neurochemistry, 1989
Abstract: In the present study, we have investigated the role of Ca2+ in the coupling of membrane depolarization to neurotransmitter secretion. We have measured (a) intracellular free Ca2+ concentration ([Ca2+Ji) changes, (b) rapid 45Ca2+uptake, and (c) Ca2+-dependent and -independent release of endogenous glutamate (Glu) and γ-aminobutyric acid (GABA) as a function of stimulus intensity by elevating the extracellular [K+] to different levels in purified ijierve terminals (synaptosomes) from rat hippocampus. Duriijg stimulation, Percoll-purined synaptosomes show an increased 45Ca2+ uptake, an elevated [Ca2+]i, and a Ca2+-dependejnt as well as a Ca2+-independent release of both Glu and GABA. With respect to both amino acids, synaptosomes respond on stimulation essentially in the same way, with maximally a fourfold increase in Ca2+-dependent (exocytotic) release. Ca2+-depen-dent transmitter release as well as [Ca2+]; elevations show maximal stimulation at moderate depolarizations (30 mM K+). A correlation exists between Ca2+-dependent release of both Glu and GABA and elevation of [Ca2+]i. C2+-dependent release is maximally stimulated with an elevation of [Ca2+]Iof 60% above steady-state levels, corresponding with an intracellular concentration of ∼400 nM, whereas elevations to 350 nM are ineffective in stimulating Ca2+-dependent release of both Glu and GABA. In contrast, Ca2+-independent release of both Glu and GABA shows roughly a linear rise with stimulus intensity up to 50 mM K+. 45Ca2+ uptake on stimulation also shows a continuous increase with stimulus intensity, although the relationship appears to be biphasic, with a plateau between 20 and 40 mM K+. These findings indicate that Ca2+-dependent, exocytotic transmitter release is not simply enhanced by larger depolarizations of the plasma membrane and that a strong Ca2+-dependent regulatory mechanism exists in synaptosomes for the trigger of exocytosis, operating at a mean [Ca2+]i of between 350 and 400 nM. Ca2+ transport and buffering mechanisms possibly involved in this regulation and the role of the membrane potential are discussed.
Presynaptic calcium channels: pharmacology and regulation
Neurochemistry international, 1995
Voltage-dependent Ca2+ channels are considered as molecular trigger elements for signal transmission at chemical synapses. Due to their central role in this fundamental process, function and pharmacology of presynaptic Ca2+ channels have recently been the subject of extensive exploration employing various experimental techniques. Several lines of evidence indicate that, at nerve terminals in higher vertebrates, the evoked influx of Ca2+ -ions is mainly mediated by Ca2+ channels of the P-type. The stringent regulation of presynaptic Ca2+ channels is supposed to be involved in fine-tuning the efficiency of synaptic transmission. Intrinsic control mechanisms, such as voltage- or Ca(2+)-dependent inactivation, or modulation of channel activity, either by G-proteins directly or via phosphorylation by protein kinases, may be of particular functional importance.