Mechanisms to separately regulate the release and recycling of synaptic vesicles – sciencedaily
Chemical synapses carry information within the nervous system. When a presynaptic cell is electrically excited, the synaptic vesicles fuse with the presynaptic membrane, causing the release of messenger substances in the vesicles in the synaptic cleft. These then bind to receptors in the postsynaptic cell where they again trigger an electrical signal. The temporal and spatial sequence of incoming signals determines how information is processed and transmitted in the brain. In order to maintain their long-term function, chemical synapses must recycle synaptic vesicles to make them available for new signal transmission.
Professor Carsten Duch and Professor Martin Heine and their respective research groups at Johannes Gutenberg University in Mainz (JGU) are studying how the release and recycling of synaptic vesicles are coordinated. “The rates of exocytosis and endocytosis at chemical synapses must be coordinated to achieve reliable signal transmission in the brain,” the biologists explained. Together with Dr Ulrich Thomas, group leader at the Leibniz Institute for Neurobiology in Magdeburg, Duch and Heine revealed in a PNAS paper how spatiotemporally separated presynaptic calcium signals independently regulate exocytosis and endocytosis of synaptic vesicles, i.e. their release and recycling.
Coexistence of different types of voltage-gated calcium channels at the presynapse level
At chemical synapses, incoming electrical impulses are converted into chemical signals and transmitted to the next cell. The process involves calcium ions first circulating through voltage-gated membrane channels in the presynapse, that is, the upstream nerve cell that transmits the signal to the postsynaptic cell. This calcium influx is tightly limited in time and space and results in exocytosis of synaptic vesicles from a specialized vesicle reservoir. Presynaptic calcium signals also regulate the recycling of synaptic vesicles, but here the temporal and spatial requirements are different. An unresolved question is how presynaptic electrical activity can lead to calcium signals with different temporal and spatial profiles in the presynaptic terminal.
By combining genetic modifications with electrophysiological and optophysiological measurements at the level of the neuromuscular synapse of the Drosophila melanogaster A genetic model organism, the research team was able to demonstrate that the presynapse harbors two different types of voltage-gated calcium channels, Cav2 and Cav1. These, however, turned out to be spatially separate. Both types of channels open when electrical signals come in, but only Cav2 channels, which reside in the active areas of the presynapse, are necessary for the exocytosis of synaptic vesicles. CaliforniavChannels 1 are located outside the active areas and increase endocytosis of synaptic vesicles via activity-dependent calcium influx. Thus, knockdown of Cav2 by means of genetic manipulation prevents synaptic transmission, while knockdown of Cav1 decreases the rate of endocytosis of synaptic vesicles, thereby increasing synaptic depression during sustained activity. Thus, calcium signals mediated by two different populations of largely independent voltage-gated calcium channels regulate two essential functions of the presynapse in response to neuronal activity, namely the release and recycling of synaptic vesicles.
Functional separation of Cav1 and Cav2 by means of a calcium pump
A key question was how calcium signals through different channels could be functionally separated at the nanoscale from the presynaptic termination, since calcium is after all a highly diffusible intracellular messenger. According to researchers, different vital functions of calcium signals by Cav1 and Cav2 channels are separated by a membrane calcium buffer. Californiav2 channels are found in the presynaptic active areas at distances of 70 to 140 nanometers from easily releasable synaptic vesicles. This distinct localization of Cav2 causes the emergence of tightly regulated calcium signals in time and space within so-called nano-domains during presynaptic electrical activity, and these are essential for temporally accurate synaptic transmission. Californiav1 localizes around active areas, theoretically allowing calcium influx simultaneously through both types of channels to produce mixed signals without measurable delay. However, mixed signals of this type are prevented by the plasma membrane calcium pump (PMCA). PMCA is located outside the active areas and isolates them from the dynamic regulation of endocytosis carried out by Cav1-mediated calcium influx. Because itv1, Cav2, and PMCA have also been identified at central synapses in the mammalian brain, these proteins may represent a conserved functional triad for separate dependent regulation of the activity of exocytosis and endocytosis of synaptic vesicles.
Calcium channels and regulation of essential synaptic functions
In the future, the Duch and Heine research groups will continue to explore the interactions of calcium channels and their associated molecules at the presynapse level. Calcium signals in the presynaptic terminus regulate other essential synaptic functions beyond exocytosis and endocytosis. These include the regulation of movement of synaptic vesicles between distinct specialized reservoirs as well as the control of fixed synaptic transmission forces, which are restored by compensatory mechanisms after disruption. This homeostatic synaptic plasticity is essential for reliably processing information in the brain. As part of a project within the Collaborative Research Center 1080 on molecular and cellular mechanisms in neuronal homeostasis, the Duch and Heine groups are studying how spatiotemporally separated presynaptic calcium signals independently control exocytosis and endocytosis, the transport of vesicles between different reservoirs and synaptic homeostasis. “Calcium signals are extremely well suited to precisely match a variety of vital synaptic functions to different neuronal activities, but we are only just beginning to determine the mechanisms that independently regulate these functions,” Duch and Heine commented on their research. in neurobiology.
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