Gliotransmission: Exocytotic release from astrocytes

Abstract

Gliotransmitters are chemicals released from glial cells fulfilling a following set of criteria: (i) they are synthesized by and/or stored in glia; (ii) their regulated release is triggered by physiological and/or pathological stimuli; (iii) they activate rapid (milliseconds to seconds) responses in neighboring cells; and (iv) they play a role in (patho)physiological processes. Astrocytes can release a variety of gliotransmitters into the extracellular space using several different mechanisms. In this review, we focus on exocytotic mechanism(s) underlying the release of three classes of gliotransmitters: (i) amino acids, such as, glutamate and d-serine; (ii) nucleotides, like adenosine 5'-triphosphate; and (iii) peptides, such as, atrial natriuretic peptide and brain-derived neurotrophic factor. It is becoming clear that astrocytes are endowed with elements that qualify them as cells communicating with neurons and other cells within the central nervous system by employing regulated exocytosis.

Figure 1

Glutamate release by Ca²⁺-dependent exocytosis. Glutamate packaged in vesicles is released from the astrocyte when the vesicle fuses with the plasma membrane. This fusion process is mediated by synaptotagmin 4 and SNARE proteins: syntaxin 1, synaptobrevin 2 and synaptosome-associated protein of 23 kDa (SNAP-23). Glutamate can be synthesized in astrocytes de novo from glucose entry to the tricarboxylic acid cycle via pyruvate carboxylase (PC). Glutamate is converted from the cycle intermediate, α-ketoglutarate (α-KG), usually by transamination of aspartate via aspartate amino transferase (AAT). The synthesized glutamate once in the cytosol can then be converted to glutamine (Gln) by glutamine synthetase (GS), or transported into vesicles via proton-dependent vesicular glutamate transporters (VGLUTs), especially isoform 3. The proton gradient is generated by vacuolar type H⁺-ATPases (V-ATPase).

Figure 2

Sources of cytosolic Ca²⁺ in vesicular release from astrocytes. Increase of cytosolic Ca²⁺ is sufficient and necessary to cause vesicular fusions and release of gliotransmitters. This process of regulated exocytosis requires the action of the ternary SNARE complex. Cytosolic Ca²⁺ accumulation could be caused by the entry of Ca²⁺ from the ER internal stores via IP₃ and ryanodine receptors (IP₃ and RyR). Store specific Ca²⁺-ATPase fills these stores, although ultimately this action requires Ca²⁺ entry from the extracellular space (ECS) through canonical type 1 transient receptor potential (TRPC1). Mitochondrial Ca²⁺ uptake is mediated by the uniporter, while free Ca²⁺within the mitochondrial matrix exits through the Na⁺/ Ca²⁺ exchanger and the mitochondrial permeability transition pore (MPTP). Drawing is not to scale.

Figure 3

Secretory pathway of peptidergic transmitters The pro-peptides are synthetized in the endoplasmic reticulum (ER). They then enter the Golgi compartments from which vesicles bud off, containing concentrated and sorted peptides. Secretory vesicles traffic away from the Golgi compartment along the secretory pathway to the plasma membrane where they dock and fuse with the plasma membrane upon a stimulus delivery, typically an increase in cytosolic Ca²⁺ levels/activity. Vesicles pinching off the plasma membrane via the endocytic pathway may be rerouted to the recycling pathway, where the substances captured from the extracellular space may be returned to the surface plasma membrane/extracellular space by entering regulated exocytosis of the secretory pathway.