Protein scaffolds in the coupling of synaptic exocytosis and endocytosis

Abstract

Communication between nerve cells largely occurs at chemical synapses -specialized sites of cell-cell contact where electrical signals trigger the exocytic release of neurotransmitter, which in turn activates postsynaptic receptor channels. The efficacy with which such chemical signals are transmitted is crucial for the functioning of the nervous system. Modulation of neurotransmission enables nerve cells to respond to a vast range of stimulus patterns. Synaptic activity can also be tremendously diverse; from the fast synapses of the hippocampus, to slow neuropeptide-containing synapses. Indeed, some signalling pathways are active in the absence of stimulation, such as those involved in the processing of sensory information, which transmit tonically at high rates of up to 100 Hz or more 1,2 .Intriguing questions arise from these facts, including how high rates of neurotransmission can be maintained over long periods of time, and what limits the ability of a given synapse to release neurotransmitter during sustained periods of activity. Recent data indicate that in many synapses, exocytosis of neurotransmitter is coupled to endocytosis, and that synapses have evolved a specialized apparatus of scaffolding proteins to comply with these demands. Such scaffolds aid the temporal and spatial coupling of exocytosis and endocytosis, and are crucial for maintaining rapid neurotransmission during sustained activity 3 .Exocytosis of neurotransmitter is triggered by stimulusinduced calcium influx into the nerve terminal 4,5 and the subsequent fusion of synaptic vesicles with the presynaptic plasma membrane at specialized regions called active zones (BOX 1). Exocytosed synaptic vesicle membrane proteins and lipids in turn are recycled at the endocytic or periactive zone (BOX 1) that surrounds the release site, to restore functional synaptic vesicle pools for reuse and to ensure long-term functionality of the synapse 6-8 (FIG. 1). Depending on the type of synapse and the stimulation frequency, several modes of endocytosis with different time constants -for example, fast and slow endocytosisseem to operate 7,9,10 . Clathrin-mediated endocytosis arguably represents the main pathway of synaptic vesicle endocytosis 6,8,11 , although other modes -for example, fast kiss-and-run exocytosis and endocytosis -could operate in parallel.Although the machineries for exocytic membrane fusion 12,13 and for endocytic retrieval of synaptic vesicle membranes have been studied separately in some detail 6,14 , comparatively little is known about the coupling between exocytosis and endocytosis. Here we synthesize recent data from physiological, morphological and biochemical studies in several model systems into hypothetical models for scaffold-based mechanisms underlying exocytic-endocytic coupling.The synaptic vesicle cycle Synaptic vesicle pools. Some defining features of chemical synapses are the presence of one or several clusters of synaptic vesicles in the presynaptic nerve terminal, and ultrastructural specializations at the pre-and postsy...

The DISABLED protein functions in CLATHRIN-mediated synaptic vesicle endocytosis and exoendocytic coupling at the active zone

“…Previous analysis in this model examined the temperature-sensitive (TS) DYNAMIN mutant shibire and revealed a rapid role for endocytic mechanisms in maintaining neurotransmitter release during synaptic activity (15,16). Subsequent work has extended these findings and showed that inhibition of DYNAMIN or AP-2 disrupts fast refilling of the release-ready synaptic vesicle pool (17)(18)(19). The results reported here demonstrate colocalization of CLATHRIN and DAB at the active zone (AZ) and provide functional and ultrastructural evidence supporting their participation in rapid CLATHRIN-dependent endocytic mechanisms that may clear neurotransmitter release sites for subsequent synaptic vesicle priming and refilling of the release-ready vesicle pool.…”

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

“…CME is important for both presynaptic and postsynaptic functions and both functions have been implicated in schizophrenia [73][74][75] . In presynaptic axon terminals, CME is required for the retrieval of synaptic vesicle proteins following neurotransmitter release, and for the recycling of vesicles back to the reserve pool 7 . Also, in presynaptic terminals, protein kinase C (PKC)-induced internalization of DAT from the synapse is clathrin-and dynamin-dependent 76 .…”

“…The route taken is, at least in part, determined by members of the Rab family of GTPases 5 , which are associated with distinct endosomal populations and which are central to ensuring that vesicle cargos find their correct destinations [6][7] .…”

Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis

“…Similar to nerve terminals, in which endocytosis supports high rates of synaptic vesicle recycling (1,2), neuroendocrine cells undergo vigorous membrane trafficking to regulate large dense-core vesicle (LDCV) release and cellular functions. However, the mechanisms by which endocytosis influences secretory function are unclear, and the molecular nature of endocytosis in these cells remains poorly understood.…”