Determinants in the β and δ Subunit Cytoplasmic Loop Regulate Golgi Trafficking and Surface Expression of the Muscle Acetylcholine Receptor

Rudell, Jolene C.; Borges, Lúcia S.; Rudell, John B.; Beck, Kenneth A.; Ferns, Michael J.

doi:10.1074/jbc.m113.502328

Cited by 13 publications

(19 citation statements)

References 31 publications

(24 reference statements)

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“…Experiments show that the presence of neural agrin combined with pervanadate, an inhibitor of tyrosine phosphatase, slow down the degradation of surface receptors in cultured muscle cells. This effect is induced by the phosphorylation of β subunit [7]. This hypothesis is supported by the finding that the mutation of β at Y390 impairs agrin-induced clustering and anchoring of AChRs in cultured myotubes [8].…”

Section: Role Of β1 Subunit In Metabolic Stability Of Nachrsmentioning

confidence: 65%

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Advances in the pharmacology of lGICs auxiliary subunits

Galaz

Barra

Figueroa

et al. 2015

Pharmacological Research

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Section: Role Of β1 Subunit In Metabolic Stability Of Nachrsmentioning

confidence: 65%

“…The authors suggest that these mechanisms regulate the surface trafficking of assembled AChRs and may avoid the surface presence of unassembled AChR subunits [7].…”

Section: Role Of β and δ Subunits In Trafficking And Achr Assemblymentioning

confidence: 99%

Advances in the pharmacology of lGICs auxiliary subunits

Galaz

Barra

Figueroa

et al. 2015

Pharmacological Research

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“…The first sequence is for the human nicotinic a 1 subunit (NP_031415.2) with a dibasic signal (Keller et al, 2001). The second and third sequences show human nicotinic b 1 (NP_033731.3) and d (NP_067611.2) and basic residues (Rudell et al, 2014). The fourth and fifth sequences show human nicotinic a 4 (NP_000735.1) and mouse b 2 (NP_033732.2) subunits.…”

Section: Resultsmentioning

confidence: 99%

Mutations in the Main Cytoplasmic Loop of the GABA_A Receptor α₄ and δ Subunits Have Opposite Effects on Surface Expression

Bracamontes¹,

Li²,

Steinbach³

2014

Mol Pharmacol

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We examined the role of putative trafficking sequences in two GABA A receptor subunits: a 4 and d. These subunits assemble with a b subunit to form a subtype of GABA A receptor involved in generating the "tonic" outward current. Both a 4 and d subunits contain dibasic retention motifs in homologous positions. When basic residues are mutated to alanine in the a 4 subunit, surface expression of epitope-tagged d subunits is increased. When basic residues in homologous regions of the d subunit are mutated, however, surface expression is reduced. We focused on the mutants that had the maximal effects to increase (in a 4 ) or reduce (in d) surface expression. The total expression of d subunits is significantly decreased by the d mutation, suggesting an effect on subunit maturation. We also examined surface expression of the b 2 subunit. Expression of the mutated a4 subunit resulted in increased surface expression of b 2 compared with wild-type a 4 , indicating enhanced forward trafficking. In contrast, mutated d resulted in decreased surface expression of b 2 compared with wild-type d and to a 4 and b 2 in the absence of any d. This observation suggests that the mutated d incorporates into multimeric receptors and reduces the overall forward trafficking of receptors. These observations indicate that the roles of trafficking motifs are complex, even when located in homologous positions in related subunits. The physiologic properties of receptors containing mutated subunits were not significantly affected, indicating that the mutations in the a 4 subunit will be useful to enhance surface expression.

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“…33,34 Moreover, dynamin-independent endocytosis of the nAChR requires Src activity, 35 although it does not appear to involve conventional endocytic tyrosine motifs in any of its 5 subunits. 36 In contrast to excitatory glutamatergic and cholinergic pathways, inhibitory neurotransmission via gamma-aminobutyric acid (GABA) appears less affected during Alzheimer's disease and GABAergic neurons seem more resistant to neurodegeneration than their excitatory counterparts. 37 Nevertheless, recent studies have found reduced levels of GABA and functionally altered GABA A receptors in Alzheimer's patients.…”

Section: Potential Role Of Sfks In Ab-and Prpinduced Neurotransmissiomentioning

confidence: 99%

Uncontrolled SFK-mediated protein trafficking in prion and Alzheimer's disease

Málaga-Trillo

Ochs

2016

Prion

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ABSTRACT. Prions and Amyloid beta (Ab) peptides induce synaptic damage via complex mechanisms that include the pathological alteration of intracellular signaling cascades. The hostencoded cellular prion protein (PrP C ) acts as a high-affinity cell surface receptor for both toxic species and it can modulate the endocytic trafficking of the N-methyl D-aspartate (NMDA) receptor and E-cadherin adhesive complexes via Src family kinases (SFKs). Interestingly, SFK-mediated control of endocytosis is a widespread mechanism used to regulate the activity of important transmembrane proteins, including neuroreceptors for major excitatory and inhibitory neurotransmitters. Here we discuss our recent work in zebrafish and accumulating evidence suggesting that subversion of this pleiotropic regulatory mechanism by Ab oligomers and prions explains diverse neurotransmission deficits observed in human patients and mouse models of prion and Alzheimer's neurodegeneration. While Ab, PrP C and SFKs constitute potential therapeutic targets on their own, drug discovery efforts might benefit significantly from aiming at protein-protein interactions that modulate the endocytosis of specific SFK targets.

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Determinants in the β and δ Subunit Cytoplasmic Loop Regulate Golgi Trafficking and Surface Expression of the Muscle Acetylcholine Receptor

Cited by 13 publications

References 31 publications

Advances in the pharmacology of lGICs auxiliary subunits

Advances in the pharmacology of lGICs auxiliary subunits

Mutations in the Main Cytoplasmic Loop of the GABA_A Receptor α₄ and δ Subunits Have Opposite Effects on Surface Expression

Uncontrolled SFK-mediated protein trafficking in prion and Alzheimer's disease

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Determinants in the β and δ Subunit Cytoplasmic Loop Regulate Golgi Trafficking and Surface Expression of the Muscle Acetylcholine Receptor

Cited by 13 publications

References 31 publications

Advances in the pharmacology of lGICs auxiliary subunits

Advances in the pharmacology of lGICs auxiliary subunits

Mutations in the Main Cytoplasmic Loop of the GABAA Receptor α4 and δ Subunits Have Opposite Effects on Surface Expression

Uncontrolled SFK-mediated protein trafficking in prion and Alzheimer's disease

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Mutations in the Main Cytoplasmic Loop of the GABA_A Receptor α₄ and δ Subunits Have Opposite Effects on Surface Expression