Golgi-independent secretory trafficking through recycling endosomes in neuronal dendrites and spines

Abstract

Neurons face the challenge of regulating the abundance, distribution and repertoire of integral membrane proteins within their immense, architecturally complex dendritic arbors. While the endoplasmic reticulum (ER) supports dendritic translation, most dendrites lack the Golgi apparatus (GA), an essential organelle for conventional secretory trafficking. Thus, whether secretory cargo is locally trafficked in dendrites through a non-canonical pathway remains a fundamental question. Here we define the dendritic trafficking itinerary for key synaptic molecules in rat cortical neurons. Following ER exit, the AMPA-type glutamate receptor GluA1 and neuroligin 1 undergo spatially restricted entry into the dendritic secretory pathway and accumulate in recycling endosomes (REs) located in dendrites and spines before reaching the plasma membrane. Surprisingly, GluA1 surface delivery occurred even when GA function was disrupted. Thus, in addition to their canonical role in protein recycling, REs also mediate forward secretory trafficking in neuronal dendrites and spines through a specialized GA-independent trafficking network.

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca 2+ /CaMKII signaling

“…A significant portion of AMPAR s are synthesized in the endoplasmic reticulum ( ER ) in dendrites possibly without TARP s, which might associate with the AMPAR core in a later secretory compartment (e.g., recycling endosomes ( RE s)) or the plasma membrane (Bowen et al, ). Surface insertion via RE s is promoted by intracellular norepinephrine ( NE ) signaling, which is transported from the extracellular space via the OCT 3 transporter first into the cytosol and then, as proposed here, into the lumen of RE s, analogous to NE transport into the Golgi apparatus (Irannejad et al, ).…”

“…Recent work shows that NE is transported into the cell and from the cytosol into the lumen of intracellular vesicles via the transporter OCT3, which allows stimulation of β ARs inside cells (Tsvetanova & von Zastrow, ; Irannejad et al, ). We propose that NE accesses the lumen of recycling endosomes (REs), which contain recycled as well as newly synthesized AMPARs (Bowen et al, ), where it stimulates the β 2 ARs associated with AMPARs to trigger S845 phosphorylation (Fig ). This phosphorylation then enhances insertion of AMPARs into the cell surface through mechanisms that are currently unknown.…”

Role of a VGF/BDNF/TrkB Autoregulatory Feedback Loop in Rapid-Acting Antidepressant Efficacy

“…However, in general, mini-Golgi stacks or Golgi ‘outposts’ (GO) can be identified in only 20% of mature hippocampal neurons, tending to be more common in developing neurons and those that overexpress membrane proteins, while endoplasmic reticulum (ER) and ER-Golgi intermediate compartment (ERGIC) are found in all dendrites (Hanus and Ehlers 2016). Locally assembled immature or mature secretory vesicles have not been shown to bud from GOs, although Golgi-independent secretion of GluA1 from dendrites can occur via non-canonical trafficking through recycling endosomes (Bowen et al 2017). In addition, immature, core-glycosylated GluA2-containing glutamate receptors have been identified on neuronal membranes (Hanus et al 2016), suggesting that membrane receptors and/or secretory proteins, some locally synthesized, could be incompletely modified post-translationally and/or processed, but could still be inserted or released, and thus could have different functional properties and turnover rates compared to their mature forms.…”

F‐actin patches associated with glutamatergic synapses control positioning of dendritic lysosomes

“…Plasticity and stability of synaptic contacts rely on several factors, including transport and delivery of proteins and mRNA from the soma, local dendritic protein synthesis, surface diffusion of membrane proteins, recycling of synaptic proteins via the dendritic secretory trafficking system, and controlled disposal of “aged” molecules mediated by lysosomes, autophagosomes, and the proteasomal system (Hanus & Schuman, ; Mikhaylova et al , ; Bowen et al , ; Goo et al , ; Nirschl et al , ; Penn et al , ; Seipold et al , ). Various secretory trafficking organelles are present along dendrites and help to regulate the protein pool required for potentiation and stabilization of specific synaptic contacts (van Bommel & Mikhaylova, ).…”