Endophilin A1 drives acute structural plasticity of dendritic spines in response to Ca2+/calmodulin

Abstract

Induction of long-term potentiation (LTP) in excitatory neurons triggers a large transient increase in the volume of dendritic spines followed by decays to sustained size expansion, a process termed structural LTP (sLTP) that contributes to the cellular basis of learning and memory. Although mechanisms regulating the early and sustained phases of sLTP have been studied intensively, how the acute spine enlargement immediately after LTP stimulation is achieved remains elusive. Here, we report that endophilin A1 orchestrates membrane dynamics with actin polymerization to initiate spine enlargement in NMDAR-mediated LTP. Upon LTP induction, Ca2+/calmodulin enhances binding of endophilin A1 to both membrane and p140Cap, a cytoskeletal regulator. Consequently, endophilin A1 rapidly localizes to the plasma membrane and recruits p140Cap to promote local actin polymerization, leading to spine head expansion. Moreover, its molecular functions in activity-induced rapid spine growth are required for LTP and long-term memory. Thus, endophilin A1 serves as a calmodulin effector to drive acute structural plasticity necessary for learning and memory.

EndophilinA-dependent coupling between activity-dependent calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation

“…We confirm this is the case for fly EndoA, but based on several biophysical methods, we do exclude large-scale Ca 2+ -induced conformational changes in EndoA. This is in agreement with recent data that also exclude direct binding of Ca 2+ to EndoA (Yang et al, 2021) and leaves open the possibility that other, as of yet unidentified, intermediary partners could be needed. Nonetheless, our data clearly show that mutating the negatively charged residue of EndoA (D265 in flies) eliminates the protein’s proper response to Ca 2+ .…”

“…EndoA is a synaptic protein involved in synaptic vesicle endocytosis (Milosevic et al, 2011; Ringstad et al, 1999; Schuske et al, 2003; Verstreken et al, 2002). Previous reports have suggested the protein is responsive to Ca 2+ , but the consequences and functional relevance of this are not known (Chen et al, 2003; Kroll et al, 2019; Yang et al, 2021; Zhang et al, 2012a). Moreover, we have previously shown that the expression of an EndoA phospho-mutant, EndoA S75A instead of wild type EndoA blocks starvation-induced synaptic autophagy (Soukup et al, 2016).…”

“…EndoA is a synaptic protein involved in synaptic vesicle endocytosis (Milosevic et al, 2011;Ringstad et al, 1999;Schuske et al, 2003;Verstreken et al, 2002). Previous reports have suggested the protein is responsive to Ca 2+ , but the consequences and functional relevance of this are not known (Chen et al, 2003;Kroll et al, 2019;Yang et al, 2021;Zhang et al, 2012a).…”

Immunofluorescence staining of phosphoinositides in primary mouse hippocampal neurons in dissociated culture

“…Following the protocol described above, we performed the PM PIP (PI3P, PI4P and PI(4,5)P 2 ) staining ( Figures 3 A–3C), and the costaining of PI(4,5)P 2 and endophilin A1 (EEN1, a peripheral membrane protein ( Yang et al., 2021 ) in neurons ( Figure 3 D). The staining results show that PI4P and PI(4,5)P 2 distribute in the PM of neurons with different patterns ( Figures 3 B and 3C).…”

The role and Mechanism of Endophilin A1 in LPS-induced Parkinson's disease model mice

“…Recent literature reports that EPA1 can act as a direct effector of Ca² /calmodulin, thereby affecting calcium homeostasis (Yang et al 2021). At the same time, EPA1 affects oxidative stress and in ammatory response (Murdoch et al 2016b; Yao et al 2014).…”