Dileucine and PDZ-binding Motifs Mediate Synaptic Adhesion-like Molecule 1 (SALM1) Trafficking in Hippocampal Neurons

Seabold, Gail K.; Wang, Philip Y.; Petralia, Ronald S.; Chang, Kai; Zhou, Arthur; McDermott, Mark I.; Wang, Yaxian; Milgram, Sharon L.; Wenthold, Robert J.

doi:10.1074/jbc.m111.279661

Cited by 13 publications

(12 citation statements)

References 73 publications

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“…This is somewhat surprising as usually di-leucine motifs are forward ER trafficking signals of G-protein coupled receptors [38]–[44]. However, the di-leucine motif of the synaptic adhesion-like molecule 1 (SALM1) also functions as ER retention signal [45]. It will be interesting to see if future studies reveal the mechanisms dictating such distinct ER trafficking responses to di-leucine motifs.…”

Section: Discussionmentioning

confidence: 99%

The Polarization of the G-Protein Activated Potassium Channel GIRK5 to the Vegetal Pole of Xenopus laevis Oocytes Is Driven by a Di-Leucine Motif

et al. 2013

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The G protein-coupled inwardly-rectifying potassium channels (known as GIRK or Kir3) form functional heterotetramers gated by G-βγ subunits. GIRK channels participate in heart rate modulation and neuronal postsynaptic inhibition in mammals. In Xenopus laevis oocytes, GIRK5 is a functional homomultimer. Previously, we found that phosphorylation of a tyrosine (Y16) at its N-terminus downregulates the surface expression of GIRK5. In this work, we elucidated the subcellular localization and trafficking of GIRK5 in oocytes. Several EGFP-GIRK5 chimeras were produced and an ECFP construct was used to identify the endoplasmic reticulum (ER). Whereas GIRK5-WT was retained in the ER at the animal pole, the phospho-null GIRK5-Y16A was localized to the vegetal pole. Interestingly, a construct with an N-terminal Δ25 deletion produced an even distribution of the channel in the whole oocyte. Through an alanine-scan, we identified an acidic cluster/di-leucine sorting-signal recognition motif between E17 and I22. We quantified the effect of each amino acid residue within this di-leucine motif in determining the distribution of GIRK5 to the animal and vegetal poles. We found that Y16 and I22 contributed to functional expression and were dominant in the polarization of GIRK5. We thus conclude that the N-terminal acidic di-leucine motif of GIRK5 determines its retention and polarized trafficking within Xl oocytes.

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Section: Discussionmentioning

confidence: 99%

The Polarization of the G-Protein Activated Potassium Channel GIRK5 to the Vegetal Pole of Xenopus laevis Oocytes Is Driven by a Di-Leucine Motif

et al. 2013

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“…[47][48][49][50] Among LRR proteins, LRFNs form a family of transmembrane cell adhesion molecules that promote changes in neuronal morphology, dendritic outgrowth and synapse formation. [51][52][53] It was further demonstrated that LRFNs form complexes with NMDARs, and promote the specialization of excitatory synapses. 24,52,53 In particular, the N-terminal domains of LFRN2 and NR1 interact directly, and this interaction regulates the surface expression of NMDARs in hippocampal neurons.…”

Section: Discussionmentioning

confidence: 99%

Heterozygous deletion of the LRFN2 gene is associated with working memory deficits

et al. 2015

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Learning disabilities (LDs) are a clinically and genetically heterogeneous group of diseases. Array-CGH and high-throughput sequencing have dramatically expanded the number of genes implicated in isolated intellectual disabilities and LDs, highlighting the implication of neuron-specific post-mitotic transcription factors and synaptic proteins as candidate genes. We report a unique family diagnosed with autosomal dominant learning disability and a 6p21 microdeletion segregating in three patients. The 870 kb microdeletion encompassed the brain-expressed gene LRFN2, which encodes for a synaptic cell adhesion molecule. Neuropsychological assessment identified selective working memory deficits, with borderline intellectual functioning. Further investigations identified a defect in executive function, and auditory-verbal processes. These data were consistent with brain MRI and FDG-PET functional brain imaging, which, when compared with controls, revealed abnormal brain volume and hypometabolism of gray matter structures implicated in working memory. We performed electron microscopy immunogold labeling demonstrating the localization of LRFN2 at synapses of cerebellar and hippocampal rat neurons, often associated with the NR1 subunit of N-methyl-D-aspartate receptors (NMDARs). Altogether, the combined approaches imply a role for LRFN2 in LD, specifically for working memory processes and executive function. In conclusion, the identification of familial cases of clinically homogeneous endophenotypes of LD might help in both the management of patients and genetic counseling for families.

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“…The identities are predominantly restricted to the extracellular regions, whereas the sequences in the C-terminals are highly variable, demonstrating virtually no amino acid sequence identities except for the PDZ-domain-binding motifs, suggesting that the individual SALMs have distinct functions (Nam et al 2011 ;Seabold et al 2012 ;Mah et al 2010 ).…”

Section: Genes and Proteinsmentioning

confidence: 96%

“…However, only SALM4 and -5 form trans -homophilic interactions. These interactions are Ca 2+ independent and highly specifi c. Thus, SALM4 does not interact with SALM5 and vice versa (Seabold et al 2012 ).…”

Section: Interactionsmentioning

confidence: 99%

Neural Cell Adhesion Molecules Belonging to the Family of Leucine-Rich Repeat Proteins

Winther

Walmod

2013

Advances in Neurobiology

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Leucine-rich repeats (LRRs) are motifs that form protein-ligand interaction domains. There are approximately 140 human genes encoding proteins with extracellular LRRs. These encode cell adhesion molecules (CAMs), proteoglycans, G-protein-coupled receptors, and other types of receptors. Here we give a brief description of 36 proteins with extracellular LRRs that all can be characterized as CAMs or putative CAMs expressed in the nervous system. The proteins are involved in multiple biological processes in the nervous system including the proliferation and survival of cells, neuritogenesis, axon guidance, fasciculation, myelination, and the formation and maintenance of synapses. Moreover, the proteins are functionally implicated in multiple diseases including cancer, hearing impairment, glaucoma, Alzheimer's disease, multiple sclerosis, Parkinson's disease, autism spectrum disorders, schizophrenia, and obsessive-compulsive disorders. Thus, LRR-containing CAMs constitute a large group of proteins of pivotal importance for the development, maintenance, and regeneration of the nervous system.

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Dileucine and PDZ-binding Motifs Mediate Synaptic Adhesion-like Molecule 1 (SALM1) Trafficking in Hippocampal Neurons

Cited by 13 publications

References 73 publications

The Polarization of the G-Protein Activated Potassium Channel GIRK5 to the Vegetal Pole of Xenopus laevis Oocytes Is Driven by a Di-Leucine Motif

The Polarization of the G-Protein Activated Potassium Channel GIRK5 to the Vegetal Pole of Xenopus laevis Oocytes Is Driven by a Di-Leucine Motif

Heterozygous deletion of the LRFN2 gene is associated with working memory deficits

Neural Cell Adhesion Molecules Belonging to the Family of Leucine-Rich Repeat Proteins

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