Vesicular release of neurotransmitter from glial cells

Vesicular release, also known as exocytosis, is the main pathway for regulated secretion of neurochemicals by neurones. Exocytosis underlies the very rapid Ca2+-dependent release of neurotransmitter in neuronal synapses as well as the much slower (also Ca2+-dependent) process of secretion of various neuro-modulators and neuro-hormones. An important feature of the exocytotic mechanism is that it is activated by local increases in intracellular Ca2+ concentration; the latter being produced either by plasmalemmal Ca2+ entry or by receptor-stimulated Ca2+ release from intracellular stores. Whatever the trigger for Ca2+ elevation, the resulting local Ca2+ signals represent the mechanism by which neurotransmitter release is coupled to stimulation, which underlies the coordinated activity of neural cells.

In all cases, elevation of cytosolic Ca2+ is an essential triggering event, but neurosecretion then depends on several processes (Figure 5.15). The whole cycle

Life Cycle Neurotransmitters

Figure 5.15 General mechanisms of exocytosis. The exocytotic cycle proceeds through several functionally distinct steps. First, the vesicles are formed in, and separated from, the Golgi complex. Subsequently vesicles accumulate transmitter, and are docked to the cellular membrane and primed for release. The act of exocytosis is triggered by local [Ca2+]i microdomains (where Ca2+ concentration may rise up to 10-100 |xM). Following exocytosis the excessive membranes are internalized via the endocytotic process and are transported back to the Golgi complex. The exocytotic process is controlled by several vesicular and plasmalemmal proteins, the most important of which are represented by syntaxin, synaptobrevin and synaptotagmin. Generation of local Ca2+ microdomains triggers conformational changes in exocytotic proteins, which results in vesicle fusion with the plasmalemma and release of vesicular contents

Figure 5.15 General mechanisms of exocytosis. The exocytotic cycle proceeds through several functionally distinct steps. First, the vesicles are formed in, and separated from, the Golgi complex. Subsequently vesicles accumulate transmitter, and are docked to the cellular membrane and primed for release. The act of exocytosis is triggered by local [Ca2+]i microdomains (where Ca2+ concentration may rise up to 10-100 |xM). Following exocytosis the excessive membranes are internalized via the endocytotic process and are transported back to the Golgi complex. The exocytotic process is controlled by several vesicular and plasmalemmal proteins, the most important of which are represented by syntaxin, synaptobrevin and synaptotagmin. Generation of local Ca2+ microdomains triggers conformational changes in exocytotic proteins, which results in vesicle fusion with the plasmalemma and release of vesicular contents begins at the level of Golgi apparatus, where the vesicles containing the neurochemicals are produced and matured. Then, the vesicles are transported to the site of release, a process known as targeting. Consequently, targeted vesicles are prepared for exocytosis by docking and priming, after which local Ca2+ elevations trigger vesicle fusion and release of secretory material. To repeat the cycle, the vesicles are retrieved from the plasmalemma, after which they return to the ER and Golgi complex.

The fusion of vesicles is controlled by several specialized proteins, located in the vesicle membrane and in the plasmalemma (Figure 5.15). The vesicle contains the actual Ca2+-sensor, synaptotagmin I, and synaptobrevin II (or vesicle-associated membrane protein 2, VAMP2); whereas the plasmalemmal counterparts are represented by syntaxin and the protein SNAP25 (synaptosome-associated protein of m.w. 25 kDa). The latter three proteins form a core of the fusion mechanism and are summarily known as SNARE proteins ('soluble N-ethylmaleimide-sensitive factor (NSF)-associated protein receptors'). When the Ca2+ concentration in the vicinity of the primed and docked vesicle is increased, the synaptotagmin is activated, which in turn stimulates the formation of the complex between synaptobrevin II from the vesicular side and syntaxin and SNAP25 from the plasma membrane side, leading to the fusion of the vesicle with the cellular membrane (Figure 5.15). Of course, this description is very much simplified and in reality many other proteins assist and fine-tune the process, yet the described core events remain obligatory for every neurosecretory event known so far.

It is now evident that astrocytes possess all the major proteins involved in exocytosis; expression of all three members of the SNARE family as well as synaptotagmin I and several auxiliary exocytotic proteins (e.g. sectetogranin, synapsin I or Rab3) has been confirmed in numerous astroglial preparations. Furthermore, astrocytes have intracellular structures similar to synaptic microvesi-cles, which are endowed with vesicle-specific proteins (synaptobrevin) and have a particularly high concentration of glutamate. Astrocytes also contain vesicular glutamate transporters (VGLUT), which accumulate glutamate within vesicles. Sometimes, these astroglial glutamate-containing vesicles are gathered in astroglial processes, although nothing similar to a presynaptic pool of vesicles characteristic for neuronal terminals has ever been observed. NG2-glia have also been shown to form synapse-like connections with neurones, but it is not known whether they have the mechanisms for vesicular release of neurotransmitter.

Most importantly, astroglial release of glutamate in response to raised intracellular Ca2+ has been demonstrated directly. This glutamate release is stimulated by

Glutamate Presynaptic Ca2

Figure 5.16 Neuronal and glial exocytosis: the source of Ca2+. The fundamental difference between transmitter release from neuronal presynaptic terminals and from glial cells lies in the source of the Ca2+ trigger. In neurones, Ca2+ enters the presynaptic terminal via activation of voltage-gated plasmalemmal channels; this ensures very rapid [Ca2+]i rise and fast exocytosis. In glial cells, Ca2+ comes from the intracellular stores, which results in a slower but more sustained [Ca2+]i increase and hence slower but more sustained release of 'gliotransmitters'

Figure 5.16 Neuronal and glial exocytosis: the source of Ca2+. The fundamental difference between transmitter release from neuronal presynaptic terminals and from glial cells lies in the source of the Ca2+ trigger. In neurones, Ca2+ enters the presynaptic terminal via activation of voltage-gated plasmalemmal channels; this ensures very rapid [Ca2+]i rise and fast exocytosis. In glial cells, Ca2+ comes from the intracellular stores, which results in a slower but more sustained [Ca2+]i increase and hence slower but more sustained release of 'gliotransmitters'

activation of astroglial metabotropic receptors, e.g. P2Y purinoreceptors, mGluRs, bradykinin, and BDNF (Trk B) receptors, and is invariably sensitive to intracellular Ca2+ elevation, as chelation of intracellular Ca2+ with membrane-permeable Ca2+-binding agents (e.g. BAPTA/AM) effectively inhibits the release.

Vesicular glutamate release from astrocytes is fundamentally different from that in neurones in respect to the source of trigger Ca2+: in astrocytes, Ca2+ comes almost exclusively from the intracellular stores, whereas neuronal exocy-tosis is governed predominantly by Ca2+ entry through plasmalemmal channels (Figure 5.16). As a consequence, vesicular release of neurotransmitter from astroglial cells develops considerably slower compared to neurones. Another important peculiarity of glial vesicular release is associated with a specific type of exocytosis found in hippocampal astrocytes: these cells may exhibit a so-called 'kiss-and-run' exocytosis, when the secretory vesicles open for a very short period of time (~2 ms) and do not completely empty their contents.

Astroglial cells may also utilize vesicular exocytosis to secrete another neurotransmitter, D-serine. D-serine is synthesized by astrocytes from L-serine using the enzyme serine racemase, and can be regarded as a specific glial neurotransmitter. D-serine activates the 'glycine' site of NMDA receptors and may play an important role in astrocyte-to-neurone signalling.

Discovery of regulated NT release from astrocytes is extremely important for our understanding of mechanisms of brain functioning, as this means that glia may be actively involved in chemical transmission, and can (as we shall see later) directly activate neuronal responses.

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Responses

  • erling lothran
    Do glial use vesicular release?
    5 years ago
  • Santina
    What does Ca2 dependent exocytosis that releases neurotransmitter at the synapse look like?
    5 years ago

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