Transport along the dendritic endoplasmic reticulum defines the trafficking modality for GABAB receptors

Abstract

In neurons, secretory organelles within the cell body are complemented by the dendritic endoplasmic reticulum (ER) and Golgi outposts (GOPs), whose role in neurotransmitter receptor trafficking is poorly understood. c-aminobutyric acid (GABA) type B metabotropic receptors (GABA B Rs) regulate the efficacy of synaptic transmission throughout the brain. Their plasma membrane availability is controlled by mechanisms involving an ER retention motif and assembly-dependent ER export. Thus, they constitute an ideal molecular model to study ER trafficking, but the extent to which the dendritic ER participates in GABA B R biosynthesis has not been thoroughly explored. Here, we show that GABA B1 localizes preferentially to the ER in dendrites and moves long distances within this compartment. Not only diffusion but also microtubule and dyneindependent mechanisms control dendritic ER transport. GABA B Rs insert throughout the somatodendritic plasma membrane but dendritic post-ER carriers containing GABA B Rs do not fuse selectively with GOPs. This study furthers our understanding of the spatial selectivity of neurotransmitter receptors for dendritic organelles.

Epilepsy and intellectual disability linked protein Shrm4 interaction with GABABRs shapes inhibitory neurotransmission

“…Kinesin-1 is responsible for GABA B1a transport through the axonal endoplasmic reticulum (ER) and ER–Golgi intermediate compartment (ERGIC25); while dynein targets GABA B1 to the dendrites26.…”

Diversifying the secretory routes in neurons

“…Biosynthesis at- and transport through- the dER is closely linked to local trafficking, constituting an early stage of protein sorting and synaptic regulation of membrane trafficking (Aridor et al, 2004 ; Jeyifous et al, 2009 ; Ramírez and Couve, 2011 ; Cui-Wang et al, 2012 ; Valenzuela et al, 2014 ). An example is the subunit α7 of nicotinic acetylcholine receptor, the trafficking of which can be locally coordinated in dendrites ER: at high levels, the Ric3 chaperone promotes ER retention and transport of α7-receptors within the dER, while at low levels it stimulates the assembly, ER release and surface expression of α7-receptors (Alexander et al, 2010 ).…”

“…Another example is the GABA B receptor (GABA B R), an heterodimeric G protein-coupled receptor (GPCRs) that regulates the slow and tonic inhibition in the brain. The GABA B1 subunit has an ER retention signal (Margeta-Mitrovic et al, 2000 ), which allows its long-range transport through the dER by a mechanism that, in addition to diffusion, involves microtubule-dependent transport (Ramírez et al, 2009 ; Valenzuela et al, 2014 ). The GABA B R traffics through both somatic and dendritic Golgi to the somatodendritic membrane (Valenzuela et al, 2014 ).…”

“…The GABA B1 subunit has an ER retention signal (Margeta-Mitrovic et al, 2000 ), which allows its long-range transport through the dER by a mechanism that, in addition to diffusion, involves microtubule-dependent transport (Ramírez et al, 2009 ; Valenzuela et al, 2014 ). The GABA B R traffics through both somatic and dendritic Golgi to the somatodendritic membrane (Valenzuela et al, 2014 ). Visualization of synchronized ER-to-Golgi trafficking of a GABA B1 mutant that lacks of the ER retention signals, revealed carriers traveling over a long distance prior to fusion with GOPs, suggesting that local dER export does not necessarily determine a local trafficking through GOPs and that different spatial ranges of ERGIC transport can regulate the local protein supply (Hanus et al, 2014 ; Valenzuela et al, 2014 ).…”

Regulation of plasma membrane expansion during axon formation

“…Together, these data suggest that immaturely glycosylated proteins might travel to the plasma membrane using a nonconventional secretory pathway that bypass the Golgi apparatus (Hanus et al, ). Newly synthesized proteins in the soma can also enter neurites through ER membranes, by lateral diffusion (Cui‐Wang et al, ) or by active dynein mediated transport (Valenzuela et al, ), since the ER network is contiguous throughout axons and dendrites. Using an ER aggregation‐inducible release system to synchronize exit of plasma membrane proteins through the secretory pathway, Bowen and colleagues showed, that at least the AMPA‐type glutamate receptor GluA1 and the postsynaptic cell adhesion molecule neuroligin 1 accumulate in RE located in dendrites and dendritic spines following ER exit.…”