Abstract
The cycle of a synaptic vesicle (SV) within the nerve terminal is a step-by-step journey with the final goal of ensuring the proper synaptic strength under changing environmental conditions. The SV cycle is a precisely regulated membrane traffic event in cells and, because of this, a plethora of membrane-bound and cytosolic proteins are devoted to assist SVs in each step of the journey. The cycling fate of endocytosed SVs determines both the availability for subsequent rounds of release and the lifetime of SVs in the terminal and is therefore crucial for synaptic function and plasticity. Molecular players that determine the destiny of SVs in nerve terminals after a round of exo-endocytosis are largely unknown. Here we review the functional role in SV fate of phosphorylation/dephosphorylation of SV proteins and of small GTPases acting on membrane trafficking at the synapse, as they are emerging as key molecules in determining the recycling route of SVs within the nerve terminal. In particular, we focus on: (i) the cyclin-dependent kinase-5 (cdk5) and calcineurin (CN) control of the recycling pool of SVs; (ii) the role of small GTPases of the Rab and ADP-ribosylation factor (Arf) families in defining the route followed by SV in their nerve terminal cycle. These regulatory proteins together with their synaptic regulators and effectors, are molecular nanomachines mediating homeostatic responses in synaptic plasticity and potential targets of drugs modulating the efficiency of synaptic transmission.
Highlights
As all GTPases, these proteins function as molecular switches by cycling between active guanosine triphosphate (GTP)-bound cdk5/CN and Rab/ADP ribosylation factor (Arf) in synaptic vesicle (SV) Fate and inactive guanosine diphosphate (GDP)-bound states. Their cycling is regulated by two families of regulatory proteins, namely guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs)
The system is highly regulated by homeostatic plasticity and represents a target for research on the molecular markers of synaptic dysfunctions and on the design of novel drugs (Shah and Lahiri, 2014; Sheng et al, 2015)
For the Rab/Arf system, we expect that additional GAP and GEF functions at the synapse will be clarified in the near future, together with the role of specific GTPase effectors in synaptic function
Summary
The synaptic vesicle (SV) cycle is the most highly regulated membrane traffic event in cells and the proteins involved, as well as the arrays of protein-protein interactions that guarantee the fidelity of the process, are getting increasingly clear. An array of CN substrates involved in the SV retrieval process are known among the main molecular actors of SV cycling (Marks and McMahon, 1998) These proteins have been collectively named dephosphins, as their dephosphorylation is induced by calcium increase during stimulation (Cousin and Robinson, 2001). Chronic silencing of firing strongly downregulates nerve terminal cdk with the result of recruiting release reluctant SVs to the recycling pool This process, which appears to be mediated by changes in the phosphorylation state of Synapsin I, can activate previously silent synapses and change the release potential of already active synapses (Kim and Ryan, 2010; Verstegen et al, 2014). Alterations of cdk activity are associated with a broad range of neurological disorders (see for reviews Cheung and Ip, 2012; McLinden et al, 2012) and in particular the cdk5-mediated homeostatic synaptic response has been recently involved in early Alzheimer’s like synaptic pathology (Sheng et al, 2015)
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