Dynamin Superfamily at Pre- and Postsynapses: Master Regulators of Synaptic Transmission and Plasticity in Health and Disease

Abstract

Dynamin superfamily proteins (DSPs) comprise a large group of GTP-ases that orchestrate membrane fusion and fission, and cytoskeleton remodeling in different cell-types. At the central nervous system, they regulate synaptic vesicle recycling and signaling-receptor turnover, allowing the maintenance of synaptic transmission. In the presynapses, these GTP-ases control the recycling of synaptic vesicles influencing the size of the ready-releasable pool and the release of neurotransmitters from nerve terminals, whereas in the postsynapses, they are involved in AMPA-receptor trafficking to and from postsynaptic densities, supporting excitatory synaptic plasticity, and consequently learning and memory formation. In agreement with these relevant roles, an important number of neurological disorders are associated with mutations and/or dysfunction of these GTP-ases. Along the present review we discuss the importance of DSPs at synapses and their implication in different neuropathological contexts.

Gain-of-Function Dynamin-2 Mutations Linked to Centronuclear Myopathy Impair Ca2+-Induced Exocytosis in Human Myoblasts

“…They comprise five functional domains: an N-terminal GTPase domain that hydrolyzes GTP, middle and GTPase effector domains that are involved in self-assembly, a pleckstrin homology domain (PH) that binds to membranes, and a C-terminal proline-rich domain (PRD) that interacts with SH3-domain-containing partners [ 4 ]. These GTPases are involved in endocytosis, caveolae internalization and membrane budding from trans-Golgi networks, as they catalyze the scission of nascent vesicles from the plasmalemma or Golgi cisterna membranes by assembling into helices that surround the neck of nascent vesicles [ 5 ]. Dynamins also regulate the dynamics of the actin cytoskeleton in different types of cells [ 6 , 7 , 8 , 9 , 10 ].…”

Gain-of-function dynamin-2 mutations linked to centronuclear myopathy impair Ca2+-induced exocytosis in human myoblasts

“…They comprise five functional domains: a N-terminal GTPase domain that hydrolyzes GTP, a middle and a GTPase effector domains that are involved in self-assembly, a pleckstrin homology domain (PH) that binds to membranes, and a C-terminal proline-rich domain (PRD) that interacts with SH3-domain-containing partners [4]. These GTPases are involved in endocytosis, caveolae internalization and membrane budding from trans-Golgi network, as they catalyze the scission of nascent vesicles from the plasmalemma or Golgi cisterna membranes by assembling into helices that surround the neck of nascent vesicles [5]. Dynamins also regulate the dynamics of the actin cytoskeleton in different types of cells [6][7][8][9][10].…”

A centronuclear myopathy-causing mutation in dynamin-2 perturbs the actin-dependent structure of dendritic spines leading to excitatory synaptic defects in a murine model of the disease

“…Dynamin super-family (DSF) is a group of large GTP-ases that act as mechano-enzymes promoting membrane remodeling in several processes including exocytosis, endocytosis, intracellular trafficking and mitochondrial dynamics among others (Ferguson, et al, 2012;Lomash, et al, 2015;Arriagada-Diaz, et al, 2020). Classical dynamins are the best understood members of the DSF.…”

“…In mammals, these are encoded by three different genes: DNM1, DNM2 and DNM3 located on chromosomes 9, 19 and 1, respectively (Newman-Smith, et al, 1997;Züchner, et al, 2005;Noakes, et al, 1999). Classical dynamins are composed by five highly conserved domains: an amino-terminal GTPase domain that binds and hydrolyze GTP, a middle structural domain, a PH-domain involved in lipid membrane interaction, a GTP-ase effector domain (GED) and an arginine-and proline-rich domain (PRD) that allows dynamin association with SH3-containing proteins (Praefcke, et al, 2004;Ferguson, et al, 2012;Antonny, et al, 2016;Singh, et al, 2017;Arriagada-Diaz, et al, 2020). These domains organize in three regions: a "bundle signaling element" (BSE) composed by helices from the GTP-ase domain and GED, a "stalk" composed by helices from the middle domain and GED, and a membrane-inserting "foot" formed by the PH domain (Chappie, et al, 2009;Faelber, et al, 2011;Ford, et al, 2011;Kong, et al, 2018).…”

“…Dynamin assembly/disassembly cycles and GTP-ase activity also regulate the bundling of the actin cytoskeleton (Gu, et al, 2010;Zhang, et al, 2020;Lin, et al, 2020;Schiffer, et al, 2015a). The three classical dynamins are expressed at the central nervous system (CNS) and play functions at the pre-and post-synapses (Arriagada-Diaz, et al, 2020). At the pre-synapses they support the endocytic recycling of synaptic vesicles (SVs), exerting differential roles depending on the pattern of neuronal activity (Tanifuji, et al, 2013).…”