Synaptic proteins as multi-sensor devices of neurotransmission

Abstract

Neuronal communication is tightly regulated in time and space. Following neuronal activation, an electrical signal triggers neurotransmitter (NT) release at the active zone. The process starts by the signal reaching the synapse followed by a fusion of the synaptic vesicle (SV) and diffusion of the released NT in the synaptic cleft. The NT then binds to the appropriate receptor and induces a membrane potential change at the target cell membrane. The entire process is controlled by a fairly small set of synaptic proteins, collectively called SYCONs. The biochemical features of SYCONs underlie the properties of NT release.SYCONs are characterized by their ability to detect and respond to changes in environmental signals. For example, consider synaptotagmin I (Syt1), a prototype of a protein family with over 20 gene and variants in mammals. Syt1 is a specific example of a multi-sensor device with a large repertoire of discrete states. Several of these states are stimulated by a local concentration of signaling molecules such as Ca2+. The ability of this protein to sense signaling molecules and to adopt multiple biochemical states is shared by other SYCONs such as the synapsins (Syns). Specific biochemical states of Syns determine the accessibility of SV for NT release. Each of these states is defined by a specific alternative spliced variant with a unique profile of phosphorylation modified sites.The plasticity of the synapse is a direct reflection of SYCON's multiple biochemical states. State transitions occurs in a wide range of time scales, and therefore these molecules need to cope with events that last milliseconds (i.e., exocytosis in fast responding synapses) and with events that can carry on for many minutes (i.e., organization of SV pools). We suggest that SYCONs are optimized throughout evolution as multi-sensor devices. A full repertoire of the switches leading to alternation of protein states and a detailed characterization of protein-protein network within the synapse is critical for the development of a dynamic model of synaptic transmission.

Correlation between afferent rearrangements and behavioral deficits after local excitotoxic insult in the mammalian vestibule: an animal model of vertigo symptoms?

“…7) and synapsin (Fig. 8), two proteins associated with synaptic vesicles (Brachya et al, 2006), in cristae at 2 h, 7 h, 12 h and 24 h after the STTK injection. In contralateral non-injured sensory epithelia (Fig.…”

“…Competition between afferent and efferent terminals for innervation of type I hair cells, with direct apposition of efferent terminals on type I hair cells, were often observed. Synaptophysin and synapsin are both required for neurotransmission, and are involved in synaptogenesis and neuronal plasticity (Brachya et al, 2006; Cesca et al, 2010). During maturation of vestibular end organs, synaptophysin and synapsin switch from a pre-synaptic and diffuse expression in hair cells with post-synaptic expression along entering fibers to a precise location at the apex of calyces, and in afferent and efferent terminals in adults (Dechesne et al, 1997; Favre et al, 1986; Gaboyard et al, 2003; Holstein et al, 2005; Scarfone et al, 1988, 1991).…”

Calcineurin-mediated Dephosphorylation of Synaptotagmin VI Is Necessary for Acrosomal Exocytosis

“…Synaptotagmins are a family of calciumbinding proteins with a central role in membrane fusion (30). These proteins interact with several factors that are important for exocytosis such as acidic phospholipids, RIM, calcium channels, and calmodulin (2,31,32). Synaptotagmin I binds individual SNAREs (33) or SNAREs assembled in binary (34 -36) or ternary complexes (37,38).…”

“…directly, the C2B domain was phosphorylated in vitro with PKC␤ II in the presence of [␥- 32 P]ATP as previously described (9). When the phosphorylated C2B domain was incubated in the presence of recombinant calcineurin, a significant dephosphorylation was observed (Fig.…”

Tandem SAM Domain Structure of Human Caskin1: A Presynaptic, Self-Assembling Scaffold for CASK

“…The presynaptic regions of neurons contain numerous multidomain proteins that organize synaptic vesicles to ensure efficient release of neurotransmitters (Chua et al, 2010; Brachya et al, 2006). CASK is one such multidomain protein which contains a calcium/calmodulin-dependent serine protein kinase domain (CaMK), two Lin-2/Lin-7 domains (L27), a PSD-95/Dlg/ZO-1 domain (PDZ), a Src homology 3 domain (SH3), and a guanylate kinase domain (GK) (Figure 1A) (Hsueh, 2006; Hata et al, 1996; Hoskins et al, 1996).…”