Pre- and post-synaptic mechanisms regulating the clustering of type A γ-aminobutyric acid receptors (GABAA receptors)

Fritschy, Jean‐Marc; Schweizer, Claude; Brünig, Ina; Lüscher, Bernhard

doi:10.1042/bst0310889

Cited by 46 publications

(25 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This data suggest that deletion of this sequence prevents the formation of links with the cytoskeletal elements that tether the receptors at the cell surface. This finding agree with Fritschy et al [2003] who hypothesized that the sorting and synaptic targeting of GABA A R is determined by interactions between specific associated proteins and appropriate sequence motifs present in particular subunits. The limitation of the lateral diffusion of GABA A R could be due to interactions with the underlying cytoskeletal network, interactions with others membrane proteins, or interactions with the extracellular matrix.…”

Section: Localisation Of the A1 Subunit Chimeras In Transfected Cos7 supporting

confidence: 93%

The M3/M4 cytoplasmic loop of the α1 subunit restricts GABA_ARs lateral mobility: A study using fluorescence recovery after photobleaching

Perán

Hooper

Boulaiz

et al. 2006

Cell Motil. Cytoskeleton

View full text Add to dashboard Cite

A crucial problem in neurobiology is how neurons are able to maintain neurotransmitter receptors at specific membrane domains. The large structural heterogeneity of gamma aminobutyric acid receptors (GABAARs) led to the hypothesis that there could be a link between GABAAR gene diversity and the targeting properties of the receptor complex. Previous studies using Fluorescence Recovery After Photobleaching (FRAP) have shown a restricted mobility in GABAARs containing the alpha1 subunit. The M3/M4 cytoplasmic loop is the region of the alpha1 subunit with the lowest sequence homology to other subunits. Therefore, we asked whether the M3/M4 loop is involved in cytoskeletal anchoring and GABAAR clustering. A series of alpha1 chimeric subunits was constructed: alpha1CH (control subunit), alpha1CD (Cytoplasmic loop deleted), alpha1CD2, and alpha1CD3 (alpha1 with the M3/M4 loop from the alpha2 and alpha3 subunits, respectively). Our results using FRAP indicate an involvement of the M3/M4 cytoplasmic loop of the alpha1 subunit in controlling receptor lateral mobility. On the other hand, inmunocytochemical approaches showed that this domain is not involved in subunit targeting to the cell surface, subunit-subunit assembly, or receptor aggregation.

show abstract

Section: Localisation Of the A1 Subunit Chimeras In Transfected Cos7 supporting

confidence: 93%

The M3/M4 cytoplasmic loop of the α1 subunit restricts GABA_ARs lateral mobility: A study using fluorescence recovery after photobleaching

Perán

Hooper

Boulaiz

et al. 2006

Cell Motil. Cytoskeleton

View full text Add to dashboard Cite

show abstract

“…The cognitive impairments lead to speculation that the dystrophin protein family may play a key role at neuronal synapses. Best evidence for such a role comes from reports that full-length dystrophin regulates the stability of selective GABA A receptors and α3-containing nAChRs at a subset of central GABAergic and peripheral sympathetic nicotinic synapses (Knuesel et al, 1999(Knuesel et al, , 2001Zaccaria et al, 2000;Del Signore et al, 2002;Levi et al, 2002;Fritschy et al, 2003). However, our findings do not support a postsynaptic role for dystrophin and utrophin proteins at nicotinic synapses in parasympathetic CG neurons.…”

Section: Discussioncontrasting

confidence: 78%

“…Dystrophin colocalizes with selective GABA A receptor subunits at a subset of inhibitory GABAergic synapses in the CNS (Knuesel et al, 1999(Knuesel et al, , 2001Fritschy et al, 2003). Dystrophin also localizes to a subset of α3-nAChR-rich postsynaptic sites in sympathetic superior cervical ganglion (SCG) neurons Zaccaria et al, 2000;Del Signore et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Dystrophin and utrophin isoforms are expressed in glia, but not neurons, of the avian parasympathetic ciliary ganglion

2008

View full text Add to dashboard Cite

Muscular dystrophy patients often show cognitive impairment, in addition to muscle degeneration caused by dystrophin gene defects. The cognitive impairments lead to speculation that the dystrophin protein family may play a key role at neuronal synapses. Dystrophin regulates the stability of selected GABA A receptor subtypes and α3-containing nicotinic acetylcholine receptors (nAChRs) at a subset of central GABAergic and peripheral sympathetic nicotinic neuron synapses. Similarly, utrophin, the autosomal homologue of dystrophin, is not required for clustering but indirectly stabilizes muscletype nAChRs at the neuromuscular junction. We examined dystrophin and utrophin expression and localization in the avian parasympathetic ciliary ganglion (CG) to determine whether these proteins play a general role at neuronal nicotinic synapses. We have determined that full-length utrophin and dystrophin and the short dystrophin isoform Dp116 are the major isoforms expressed in the CG based on immunoblotting and immunolabeling. Unexpectedly, the cytoskeletal proteins were not detected at nicotinic synapses or in CG neurons. They are expressed in myelinating and non-myelinating Schwann cells. Further, utrophin expression developmentally precedes that of dystrophin. The proteins show partially overlapping distributions, but also differential accumulation along the surface membrane of Schwann cells adjacent to neuronal somata versus axonal processes. Our findings are consistent with reports that dystrophin protein family members function in the maintenance of cellcell interactions and myelination by anchoring the Schwann cell surface membrane to the basal lamina. In contrast, our results differ from those in skeletal muscle and a subset of sympathetic neurons where utrophin and dystrophin localize at nicotinic synapses.

show abstract

“…[45][46][47][48] According to various studies this dystrophin isoform has a stabilizing effect on the GABA receptors by limiting their lateral diffusion outside the synapse. 49,50 Importance of GABA receptors for the regulation of cognition, emotion and memory is increasingly being recognized. 51,52 The Dp427p is expressed in the cerebellar and hippocampal Purkinje cells and in the cortical brain.…”

Section: Discussionmentioning

confidence: 99%

The dystrophin gene and cognitive function in the general population

et al. 2014

View full text Add to dashboard Cite

The aim of our study is to investigate whether single-nucleotide dystrophin gene (DMD) variants associate with variability in cognitive functions in healthy populations. The study included 1240 participants from the Erasmus Rucphen family (ERF) study and 1464 individuals from the Rotterdam Study (RS). The participants whose exomes were sequenced and who were assessed for various cognitive traits were included in the analysis. To determine the association between DMD variants and cognitive ability, linear (mixed) modeling with adjustment for age, sex and education was used. Moreover, Sequence Kernel Association Test (SKAT) was used to test the overall association of the rare genetic variants present in the DMD with cognitive traits. Although no DMD variant surpassed the prespecified significance threshold (Po1 × 10 − 4 ), rs147546024:A4G showed strong association (β = 1.786, P-value = 2.56 × 10 − 4 ) with block-design test in the ERF study, while another variant rs1800273:G4A showed suggestive association (β = − 0.465, P-value = 0.002) with Mini-Mental State Examination test in the RS. Both variants are highly conserved, although rs147546024:A4G is an intronic variant, whereas rs1800273:G4A is a missense variant in the DMD which has a predicted damaging effect on the protein. Further gene-based analysis of DMD revealed suggestive association (P-values = 0.087 and 0.074) with general cognitive ability in both cohorts. In conclusion, both single variant and gene-based analyses suggest the existence of variants in the DMD which may affect cognitive functioning in the general populations.

show abstract

Pre- and post-synaptic mechanisms regulating the clustering of type A γ-aminobutyric acid receptors (GABAA receptors)

Cited by 46 publications

References 46 publications

The M3/M4 cytoplasmic loop of the α1 subunit restricts GABA_ARs lateral mobility: A study using fluorescence recovery after photobleaching

The M3/M4 cytoplasmic loop of the α1 subunit restricts GABA_ARs lateral mobility: A study using fluorescence recovery after photobleaching

Dystrophin and utrophin isoforms are expressed in glia, but not neurons, of the avian parasympathetic ciliary ganglion

The dystrophin gene and cognitive function in the general population

Contact Info

Product

Resources

About

Pre- and post-synaptic mechanisms regulating the clustering of type A γ-aminobutyric acid receptors (GABAA receptors)

Cited by 46 publications

References 46 publications

The M3/M4 cytoplasmic loop of the α1 subunit restricts GABAARs lateral mobility: A study using fluorescence recovery after photobleaching

The M3/M4 cytoplasmic loop of the α1 subunit restricts GABAARs lateral mobility: A study using fluorescence recovery after photobleaching

Dystrophin and utrophin isoforms are expressed in glia, but not neurons, of the avian parasympathetic ciliary ganglion

The dystrophin gene and cognitive function in the general population

Contact Info

Product

Resources

About

The M3/M4 cytoplasmic loop of the α1 subunit restricts GABA_ARs lateral mobility: A study using fluorescence recovery after photobleaching

The M3/M4 cytoplasmic loop of the α1 subunit restricts GABA_ARs lateral mobility: A study using fluorescence recovery after photobleaching