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

Ramírez, Omar; Vidal, René L.; Tello, Judith A.; Vargas, Karina J.; Kindler, Stefan; Härtel, Steffen; Couve, Andrés

doi:10.1074/jbc.m900575200

Cited by 36 publications

(46 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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: 80%

See 1 more Smart Citation

The Sushi Domains of GABA_BReceptors Function as Axonal Targeting Signals

Biermann¹,

Ivankova-Susankova²,

Bradaı̈a³

et al. 2010

J. Neurosci.

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 80%

“…It is therefore conceivable that GABA B1a traffics into axons within the ER. As previously reported (Ramírez et al, 2009), we found a partial colocalization of transfected GABA B1a subunits with the ER in the somatodendritic compartment using an ER-targeted GFP (Aoki et al, 2002) as a marker (supplemental Fig. S2, available at www.…”

Section: Resultssupporting

confidence: 56%

The Sushi Domains of GABA_BReceptors Function as Axonal Targeting Signals

Biermann¹,

Ivankova-Susankova²,

Bradaı̈a³

et al. 2010

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…ACTL6B, encoding Actin-like 6B (also known as BAF53B), is a pivotal co-factor for the SWI/SNF neuron-specific chromatin remodeling complex nBAF, which is required for neural development and dendritic outgrowth. 27,28 Also, GABBR2, which is a component of the G proteincoupled GABA receptor, plays a critical role in the fine-tuning of inhibitory synaptic transmission, [29][30][31] and other members of the GABA receptor family have already been conclusively linked to neurodevelopmental disorders. 32,33 GABBR2 was very recently also reported by others to show significant de novo mutation clustering in a neurodevelopmental cohort.…”

mentioning

confidence: 99%

Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes

Lelieveld

Wiel

Venselaar

et al. 2017

The American Journal of Human Genetics

101

View full text Add to dashboard Cite

SummaryHaploinsufficiency (HI) is the best characterized mechanism through which dominant mutations exert their effect and cause disease. Non-haploinsufficiency (NHI) mechanisms, such as gain-of-function and dominant-negative mechanisms, are often characterized by the spatial clustering of mutations, thereby affecting only particular regions or base pairs of a gene. Variants leading to haploinsufficency might occasionally cluster as well, for example in critical domains, but such clustering is on the whole less pronounced with mutations often spread throughout the gene. Here we exploit this property and develop a method to specifically identify genes with significant spatial clustering patterns of de novo mutations in large cohorts. We apply our method to a dataset of 4,061 de novo missense mutations from published exome studies of trios with intellectual disability and developmental disorders (ID/DD) and successfully identify 15 genes with clustering mutations, including 12 genes for which mutations are known to cause neurodevelopmental disorders. For 11 out of these 12, NHI mutation mechanisms have been reported. Additionally, we identify three candidate ID/DD-associated genes of which two have an established role in neuronal processes. We further observe a higher intolerance to normal genetic variation of the identified genes compared to known genes for which mutations lead to HI. Finally, 3D modeling of these mutations on their protein structures shows that 81% of the observed mutations are unlikely to affect the overall structural integrity and that they therefore most likely act through a mechanism other than HI.De novo mutations affecting protein-coding genes are a major cause of intellectual disability (ID) and other developmental disorders (DDs). We downloaded all DNMs occurring in individuals with ID/DD from de novo-db version 1.3 14 identified through WES and whole genome sequencing which were then reannotated with our in-house variant annotation pipeline. The de novo mutations included in the analysis were previously validated by a second independent method or showed a high validation rate for a subset of de novo mutations. In addition, we added 1,183 de novo variants identified in the exomes of an in-house ID cohort that was previously published. 8 To further reduce the risk of including sequencing artifacts and/or genotyping errors, we excluded all de novo variants that were present more than once in the ExAC dataset (Table S1). 15 These efforts resulted in 6,495 protein coding DNMs, including 4,061 missense mutations, in 5,302 individuals with ID/DD (Table S2). We set out to determine for any gene whether the observed de novo missense mutations cluster more than expected compared to random permutations. Hereto, we selected for each the longest representative transcript (i.e., part of the GENCODE basic set) 16 and calculated the geometric mean distance d g over all missense DNMs on

show abstract

“…However, segregated GABA B1 and GABA B2 subunits are detected by light and electron microscopy in hippocampal and visual cortex neurons (Gonchar et al, 2001;Ramírez et al, 2009;Biermann et al, 2010). Because GABA B1 is exported from the ER only upon binding to GABA B2 this evidence suggests that they utilize an alternative ER transport pathway into dendrites during the early stages of their biosynthetic itinerary.…”

Section: Introductionmentioning

confidence: 98%

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

Valenzuela

Jaureguiberry‐Bravo

Salas

et al. 2014

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 36 publications

References 47 publications

The Sushi Domains of GABA_BReceptors Function as Axonal Targeting Signals

The Sushi Domains of GABA_BReceptors Function as Axonal Targeting Signals

Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes

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

Contact Info

Product

Resources

About

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

Cited by 36 publications

References 47 publications

The Sushi Domains of GABABReceptors Function as Axonal Targeting Signals

The Sushi Domains of GABABReceptors Function as Axonal Targeting Signals

Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes

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

Contact Info

Product

Resources

About

The Sushi Domains of GABA_BReceptors Function as Axonal Targeting Signals

The Sushi Domains of GABA_BReceptors Function as Axonal Targeting Signals