Regulated exocytosis in astrocytic signal integration

Abstract

Astrocytes can be considered as signal integrators in central nervous system activity. These glial cells can respond to signals from the heterocellular milieu of the brain and subsequently release various molecules to signal to themselves and/or other neighboring neural cells. An important functional module that enables signal integration in astrocytes is exocytosis, a Ca(2+)-dependent process consisting of vesicular fusion to the plasma membrane. Astrocytes utilize regulated exocytosis to release various signaling molecules stored in the vesicular lumen. Here we review the properties of exocytotic release of three classes of gliotransmitters: (i) amino acids, (ii) nucleotides and (iii) peptides. Vesicles may carry not only lumenal cargo, but also membrane-associated molecules. Therefore, we also discuss exocytosis as a delivery mechanism for transporters and receptors to the plasma membrane, where these proteins are involved in astrocytic intercellular signaling.

Figure 1

Regulated exocytosis in astrocytes. Ca²⁺-dependent exocytosis is a mechanism underlying the release of three classes of gliotransmitters: amino acids (AA), nucleotides (e.g., ATP), and peptides from astrocytes. These chemical transmitters are stored in and released from at least two distinct classes of vesicles (clear and dense core) at the plasma membrane. Secretory vesicles can also carry membrane-associated molecules. Delivery of membrane signaling receptors, such as the G-protein coupled receptors (GPCRs) and transporters, such as the excitatory amino acid transporters (EAATs) to the plasma membrane is of special interest for astrocytic interactions with other neural cells. Arrows indicate direction of vesicle trafficking. Dashed arrow indicates the presumed recycling of ATP/peptide, GPCR, and EAAT containing vesicles. Ext, extracellular space; Int, intracellular space; Nuc, nucleus. Drawing is not to scale.

Figure 2

Multiple sources of cytosolic Ca²⁺ that contribute to vesicular release from astrocytes. Vesicles (ves) fuse to the plasma membrane and release gliotransmitters. This process of regulated exocytosis is governed by the action of the ternary SNARE complex and is triggered by a preceding increase of cytosolic Ca²⁺. Cytosolic Ca²⁺ accumulation is predominately caused by the entry of Ca²⁺ from endoplasmic reticulum (ER) internal stores via ryanodine and inositol 1,4,5-trisphosphate receptors (RyR and IP3R, respectively). Store-specific Ca²⁺-ATPase (SERCA) fills these stores, which requires Ca²⁺ entry from the extracellular space (Ext) through store-operated Ca²⁺ channels (SOC) located at the plasma membrane. Mitochondria (Mito) represent a source/sink of cytosolic Ca²⁺; uptake is mediated by the uniporter, efflux occurs via the Na⁺/Ca²⁺ exchanger and the mitochondrial permeability transition pore (MPTP). Int, intracellular space; Nuc, nucleus. Drawing is not to scale.