News about non-secretory exocytosis: mechanisms, properties, and functions

Abstract

The fusion by exocytosis of many vesicles to the plasma membrane induces the discharge to the extracellular space of their abundant luminal cargoes. Other exocytic vesicles, however, do not contain cargoes, and thus, their fusion is not followed by secretion. Therefore, two distinct processes of exocytosis exist, one secretory and the other non-secretory. The present review deals with the knowledge of non-secretory exocytosis developed during recent years. Among such developments are the dual generation of the exocytic vesicles, initially released either from the trans-Golgi network or by endocytosis; their traffic with activation of receptors, channels, pumps, and transporters; the identification of their tethering and soluble N-ethylmaleimide-sensitive factor attachment protein receptor complexes that govern membrane fusions; the growth of axons and the membrane repair. Examples of potential relevance of these processes for pathology and medicine are also reported. The developments presented here offer interesting chances for future progress in the field.

Keywords: Golgi complex; endocytosis; exocytosis; vesicles.

Figure 1

Transport and non-secretory exocytosis of vesicles positive for receptor subunits in neurons. (A) The traffic of two receptor subunits, GluA2 of the stimulatory AMPA receptor and γ2S of the inhibitory GABA_A receptor, in resting hippocampal pyramidal neurons. The two subunits, released from the TGN in distinct vesicles (blue and green), move to different sites of the plasma membrane: dendrites (den) for GluA2; the cell body (cb) for γ2S. The subsequent exocytic fusion of the two subunit-positive vesicles occurs with SNARE complexes different for t-SNARE, SNAP25, and SNAP23, respectively. (B) The traffic of two AMPA subunits in the same dendrite, taking place during stimulation. GluA1 (blue), transported by a vesicle addressed to the dendritic spine near the dense protein complex, moves rapidly to the postsynaptic membrane. GluA2 (violet), which has been transported by a vesicle addressed to a dendritic site away from the spine, moves along the plasma membrane towards the spine, reaching it, however, after some time. Interestingly, the SNARE complex used by GluA-positive vesicles in stimulated neurons is different from the complex used by GluA-positive vesicles in the same neurons at rest.

Figure 2

Non-secretory exocytosis of endocytic origin. (A) After endocytosis (Endo, violet), most endocytic vesicles and tubules are spread in the cytoplasm, where some of them fuse with lysosomes (Ly, green). A fraction of these organelles, however, proceeds to the plasma membrane, either directly (1) or after fusion with the TGN (2), by processes designed as recycling. The exocytic fusion (Exo, blue) of recycled organelles takes place by two alternative SNARE complexes. (B) Events that appear in adipocytes and muscle fibers upon stimulation (stim) by insulin (Ins). A population of GSV vesicles (blue), enriched in the transporter GLUT4, is concentrated near the nucleus of resting cells. After insulin stimulation, the GSVs move (1) to the proximity of the plasma membrane. The ensuing GSV exocytosis (blue) induces great increase of GLUT4 at the cell surface, with ensuing marked increase of glucose uptake by the cell. The exocytized GLUT4-rich vesicles are then taken up by the endocytosis process of the cell (violet, 2) followed by the conversion of endosomes into GSVs (3), the vesicles ready to be re-exocytized upon continued or re-stimulation of the cell by insulin. (C) The role of non-secretory exocytosis in cytokinesis, the final step of mitosis. This process, resulting in the detachment of the two daughter cells, requires the participation of many vesicles (blue) of endocytic origin, which are first concentrated in the cleavage furrow along the central spindle of the cell, and then fuse locally to the plasma membrane.

Figure 3

Axon growth requires non-secretory exocytosis during neuronal development. This figure illustrates three steps of axon growth in the same cultured neuron. (A) The axon just starts to increase its length. At its tip (enlarged on the right), the growth cone is filled with moderately large vesicles (blue) that undergo intense non-secretory exocytosis followed by some endocytosis (violet). A consequence is a progressive elongation of the fiber. (B) A few days later, the length of the axon is significantly increased. At the growth cone, the less numerous vesicles undergoing non-secretory exocytosis coexist with groups of small synaptic vesicles (red) undergoing rapid secretory exocytosis, followed by endocytosis. (C) In the neuron cultured for several days, the growth cone is further grown up. However, non-secretory exocytosis (blue) have almost disappeared, while synaptic cycles (secretory exocytosis of small vesicles, red, followed by endocytosis) have increased, both at the cone (shown on the right) and at earlier sites along the axon (not shown).