Marlin-1 and conventional kinesin link GABAB receptors to the cytoskeleton and regulate receptor transport

Vidal, René L.; Ramírez, Omar; Sandoval, Lisette; Koenig‐Robert, Roger; Härtel, Steffen; Couve, Andrés

doi:10.1016/j.mcn.2007.04.008

Cited by 29 publications

(40 citation statements)

References 44 publications

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“…Both the C-terminal domain of the GABA B1 and GABA B2 subunits contain a number of putative dendritic targeting signals. It was recently proposed that GABA B1 and GABA B2 subunits are transported into dendrites while still residing in the ER and before assembly into heteromeric complexes (Vidal et al, 2007;Ramírez et al, 2009). Consistent with this proposal, we found a colocalization of transfected GABA B1 protein with ER-targeted GFP.…”

Section: Discussionsupporting

confidence: 91%

The Sushi Domains of GABA_BReceptors Function as Axonal Targeting Signals

Biermann¹,

Ivankova-Susankova²,

Bradaı̈a³

et al. 2010

J. Neurosci.

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GABA B receptors are the G-protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the brain. Two receptor subtypes, GABA B(1a,2) and GABA B(1b,2) , are formed by the assembly of GABA B1a and GABA B1b subunits with GABA B2 subunits. The GABA B1b subunit is a shorter isoform of the GABA B1a subunit lacking two N-terminal protein interaction motifs, the sushi domains. Selectively GABA B1a protein traffics into the axons of glutamatergic neurons, whereas both the GABA B1a and GABA B1b proteins traffic into the dendrites. The mechanism(s) and targeting signal(s) responsible for the selective trafficking of GABA B1a protein into axons are unknown. Here, we provide evidence that the sushi domains are axonal targeting signals that redirect GABA B1a protein from its default dendritic localization to axons. Specifically, we show that mutations in the sushi domains preventing protein interactions preclude axonal localization of GABA B1a . When fused to CD8␣, the sushi domains polarize this uniformly distributed protein to axons. Likewise, when fused to mGluR1a the sushi domains redirect this somatodendritic protein to axons, showing that the sushi domains can override dendritic targeting information in a heterologous protein. Cell surface expression of the sushi domains is not required for axonal localization of GABA B1a . Altogether, our findings are consistent with the sushi domains functioning as axonal targeting signals by interacting with axonally bound proteins along intracellular sorting pathways. Our data provide a mechanistic explanation for the selective trafficking of GABA B(1a,2) receptors into axons while at the same time identifying a well defined axonal delivery module that can be used as an experimental tool.

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Section: Discussionsupporting

confidence: 91%

The Sushi Domains of GABA_BReceptors Function as Axonal Targeting Signals

Biermann¹,

Ivankova-Susankova²,

Bradaı̈a³

et al. 2010

J. Neurosci.

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“…Immunofluorescence, Cell Fractionation, and Immunoprecipitation-These methodologies were performed as described previously (25,26).…”

Section: Methodsmentioning

confidence: 99%

“…M 1 and M 2 can be understood as the amount of colocalizing signal relative to the total amount of segmented signal. FRAP experiments were performed at ambient temperature in a 23°C equilibrated microscopy suite as described previously (25). Dendritic ROIs of 100 m 2 , 15 m away from the soma, were bleached for 8 s with the argon 488 nm laser at 100% power.…”

Section: Methodsmentioning

confidence: 99%

Dendritic Assembly of Heteromeric γ-Aminobutyric Acid Type B Receptor Subunits in Hippocampal Neurons

Ramírez

Vidal

Tello

et al. 2009

Journal of Biological Chemistry

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Understanding the mechanisms that control synaptic efficacy through the availability of neurotransmitter receptors depends on uncovering their specific intracellular trafficking routes. ␥-Aminobutyric acid type B (GABA B ) receptors (GABA B Rs) are obligatory heteromers present at dendritic excitatory and inhibitory postsynaptic sites. It is unknown whether synthesis and assembly of GABA B Rs occur in the somatic endoplasmic reticulum (ER) followed by vesicular transport to dendrites or whether somatic synthesis is followed by independent transport of the subunits for assembly and ER export throughout the somatodendritic compartment. To discriminate between these possibilities we studied the association of GABA B R subunits in dendrites of hippocampal neurons combining live fluorescence microscopy, biochemistry, quantitative colocalization, and bimolecular fluorescent complementation. We demonstrate that GABA B R subunits are segregated and differentially mobile in dendritic intracellular compartments and that a high proportion of non-associated intracellular subunits exist in the brain. Assembled heteromers are preferentially located at the plasma membrane, but blockade of ER exit results in their intracellular accumulation in the cell body and dendrites. We propose that GABA B R subunits assemble in the ER and are exported from the ER throughout the neuron prior to insertion at the plasma membrane. Our results are consistent with a bulk flow of segregated subunits through the ER and rule out a post-Golgi vesicular transport of preassembled GABA B Rs.

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“…For example, dendritic traffi cking of NMDARs is dependent on the scaffold proteins CASK and SAP97, which form complexes with motor proteins and sort receptors to ER and Golgi outposts for plasma membrane delivery (Jeyifous et al, 2009). Likewise, a dominant negative KIF5 alters the intracellular localization of ER retained wild-type GABA B R1 but not of a subunit with mutations in the ER retention motif (Vidal et al, 2007). The role of molecular motors in ER transport along dendrites is further supported by evidence indicating that resident proteins of the ER move from the soma to dendrites in a microtubule and kinesin-dependent manner (Bannai et al, 2004;Copray et al, 1996;Vlachos et al, 2009).…”

Section: Dendritic Er Transport and Export As A Mechanism To Reach DImentioning

confidence: 93%

Location matters: the endoplasmic reticulum and protein trafficking in dendrites

2011

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Neurons are highly polarized, but the traffi cking mechanisms that operate in these cells and the topological organization of their secretory organelles are still poorly understood. Particularly incipient is our knowledge of the role of the neuronal endoplasmic reticulum. Here we review the current understanding of the endoplasmic reticulum in neurons, its structure, composition, dendritic distribution and dynamics. We also focus on the traffi cking of proteins through the dendritic endoplasmic reticulum, emphasizing the relevance of transport, retention, assembly of multi-subunit protein complexes and export. We additionally discuss the roles of the dendritic endoplasmic reticulum in synaptic plasticity.Running title: structure and function of the dendritic endoplasmic reticulum.

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Marlin-1 and conventional kinesin link GABAB receptors to the cytoskeleton and regulate receptor transport

Cited by 29 publications

References 44 publications

The Sushi Domains of GABA_BReceptors Function as Axonal Targeting Signals

The Sushi Domains of GABA_BReceptors Function as Axonal Targeting Signals

Dendritic Assembly of Heteromeric γ-Aminobutyric Acid Type B Receptor Subunits in Hippocampal Neurons

Location matters: the endoplasmic reticulum and protein trafficking in dendrites

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Marlin-1 and conventional kinesin link GABAB receptors to the cytoskeleton and regulate receptor transport

Cited by 29 publications

References 44 publications

The Sushi Domains of GABABReceptors Function as Axonal Targeting Signals

The Sushi Domains of GABABReceptors Function as Axonal Targeting Signals

Dendritic Assembly of Heteromeric γ-Aminobutyric Acid Type B Receptor Subunits in Hippocampal Neurons

Location matters: the endoplasmic reticulum and protein trafficking in dendrites

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The Sushi Domains of GABA_BReceptors Function as Axonal Targeting Signals

The Sushi Domains of GABA_BReceptors Function as Axonal Targeting Signals