Role of Bassoon and Piccolo in Assembly and Molecular Organization of the Active Zone

Abstract

Bassoon and Piccolo are two very large scaffolding proteins of the cytomatrix assembled at the active zone (CAZ) where neurotransmitter is released. They share regions of high sequence similarity distributed along their entire length and seem to share both overlapping and distinct functions in organizing the CAZ. Here, we survey our present knowledge on protein-protein interactions and recent progress in understanding of molecular functions of these two giant proteins. These include roles in the assembly of active zones (AZ), the localization of voltage-gated Ca2+ channels (VGCCs) in the vicinity of release sites, synaptic vesicle (SV) priming and in the case of Piccolo, a role in the dynamic assembly of the actin cytoskeleton. Piccolo and Bassoon are also important for the maintenance of presynaptic structure and function, as well as for the assembly of CAZ specializations such as synaptic ribbons. Recent findings suggest that they are also involved in the regulation activity-dependent communication between presynaptic boutons and the neuronal nucleus. Together these observations suggest that Bassoon and Piccolo use their modular structure to organize super-molecular complexes essential for various aspects of presynaptic function.

Trio, a Rho Family GEF, Interacts with the Presynaptic Active Zone Proteins Piccolo and Bassoon

“…AZ proteins are thought to function in concert with trans-synaptic cell-adhesion molecules (CAMs) to define sites of neurotransmitter release, holding them in register with the postsynaptic density (PSD) [1, 2]. In addition, they are thought to precisely coordinate aspects of the synaptic vesicle (SV) cycle [3] such as the translocation of SVs from the reserve to the readily releasable pool, and SV exocytosis/endocytosis [1].…”

“…Ultrastructural studies of excitatory and inhibitory synapses suggest that, similar to other membrane specializations [4], AZs are delineated by a collection of scaffold/cytoskeletal proteins [2]. The molecular analysis of the CAZs has lead to the identification of a number of large multi-domain proteins [1].…”

“…One group, including Munc13 and RIM1α have been linked to the priming of SVs during exocytosis at the AZ as well as short and long-term forms of presynaptic plasticity [5]. A second group, including ELKS (also referred to as ERCs or CAST), Liprin, Bassoon, and Piccolo, have been implicated in the structural assembly of the AZ, creating a lattice that guides SVs to neurotransmitter release sites [2]. For example, the loss of Liprin/SYD2 in C .…”

“…In the case of Piccolo and Bassoon, their large size, multi-domain nature, and early arrival at nascent synapses suggests they play a fundamental role in the assembly of the AZ [2]. Although the individual loss of Piccolo [12, 13] or Bassoon [14] from synapses does not cause major defects of AZ assembly, the simultaneous loss of both these proteins from hippocampal neurons in culture induces ubiquitination and degradation of presynaptic proteins, suggesting a shared role for both proteins in synaptic integrity [15].…”

“…However, unlike Piccolo, there is no report implicating Bassoon in AZ F-actin assembly. Therefore, Piccolo and Bassoon, through their multi-domain structure, have unique and shared functions regulating molecular AZ processes [2]. …”