The Importance of TM3-4 Loop Subdomains for Functional Reconstitution of Glycine Receptors by Independent Domains

Unterer, Bea; Becker, Cord‐Michael; Villmann, Carmen

doi:10.1074/jbc.m112.376053

Cited by 14 publications

(21 citation statements)

References 36 publications

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“…The reduced glycine sensitivity was only partly compensated by co-expressing the ␤ wild type subunit. This result strongly suggests that the truncated subunit is incorporated into functional receptors, which is unexpected given that previous GlyR studies indicated that TM4 deletion is incompatible with the surface expression of functional ␣1 GlyRs (32)(33)(34)(35). Given our unexpected result, we sought to confirm whether the p.E375X mutant subunit was incorporated into functional GlyRs using voltage clamp fluorometry.…”

Section: Resultsmentioning

confidence: 87%

“…We also attempted to confirm it using immunofluorescence, but the incorporation rate may have been too low to allow surface expression to be detected. As noted above, we were surprised that the p.E375X subunit was incorporated, given that previous studies have shown that TM4 deletion is incompatible with the surface expression of functional ␣1 GlyRs (32)(33)(34)(35). Indeed, the deletion of only a few residues at the C-terminal end of the TM4 domain is sufficient to render some pLGIC receptors completely nonfunctional (12,44,45).…”

Section: Discussionmentioning

confidence: 99%

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New Hyperekplexia Mutations Provide Insight into Glycine Receptor Assembly, Trafficking, and Activation Mechanisms

Bode

Wood

Mullins

et al. 2013

Journal of Biological Chemistry

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Background: Hyperekplexia mutations have provided much information about glycine receptor structure and function. Results: We identified and characterized nine new mutations. Dominant mutations resulted in spontaneous activation, whereas recessive mutations precluded surface expression. Conclusion: These data provide insight into glycine receptor activation mechanisms and surface expression determinants. Significance: The results enhance our understanding of hyperekplexia pathology and glycine receptor structure-function.

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Section: Resultsmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

New Hyperekplexia Mutations Provide Insight into Glycine Receptor Assembly, Trafficking, and Activation Mechanisms

Bode

Wood

Mullins

et al. 2013

Journal of Biological Chemistry

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“…Following 48 h post-transfection, biotinylation experiments were performed from transfected HEK293 cells as described previously [11]. Whole cell and surface fractions were stained using MAb4A for GlyR␣ receptor protein and a pan-cadherin antibody (Cell Signaling, Danvers, MA, USA) to stain cadherin as a membrane marker.…”

Section: Biotinylation Of Cell Surface Proteinmentioning

confidence: 99%

Length of the TM3-4 loop of the glycine receptor modulates receptor desensitization

Langlhofer

Janzen

Meiselbach

et al. 2015

Neuroscience Letters

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“…The Gly receptor domain architecture does also allow for the generation of a functional inhibitory neurotransmitter receptor from three independent domains. The co‐expression of the lacking M3–M4 loop in addition to the truncated N‐ and C‐terminal Gly receptor α1 protein fragments again resulted in the rescue of channel function (Figure C) (Unterer et al ., ).…”

Section: Domain Co‐expression: a Way To Rescue Protein Functionmentioning

confidence: 97%

Glycine receptor mouse mutants: model systems for human hyperekplexia

Schaefer

Langlhofer

Kluck

et al. 2013

British J Pharmacology

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Human hyperekplexia is a neuromotor disorder caused by disturbances in inhibitory glycine-mediated neurotransmission. Mutations in genes encoding for glycine receptor subunits or associated proteins, such as GLRA1, GLRB, GPHN and ARHGEF9, have been detected in patients suffering from hyperekplexia. Classical symptoms are exaggerated startle attacks upon unexpected acoustic or tactile stimuli, massive tremor, loss of postural control during startle and apnoea. Usually patients are treated with clonazepam, this helps to dampen the severe symptoms most probably by up-regulating GABAergic responses. However, the mechanism is not completely understood. Similar neuromotor phenotypes have been observed in mouse models that carry glycine receptor mutations. These mouse models serve as excellent tools for analysing the underlying pathomechanisms. Yet, studies in mutant mice looking for postsynaptic compensation of glycinergic dysfunction via an up-regulation in GABAA receptor numbers have failed, as expression levels were similar to those in wild-type mice. However, presynaptic adaptation mechanisms with an unusual switch from mixed GABA/glycinergic to GABAergic presynaptic terminals have been observed. Whether this presynaptic adaptation explains the improvement in symptoms or other compensation mechanisms exist is still under investigation. With the help of spontaneous glycine receptor mouse mutants, knock-in and knock-out studies, it is possible to associate behavioural changes with pharmacological differences in glycinergic inhibition. This review focuses on the structural and functional characteristics of the various mouse models used to elucidate the underlying signal transduction pathways and adaptation processes and describes a novel route that uses gene-therapeutic modulation of mutated receptors to overcome loss of function mutations. AbbreviationsCLR, cys-loop receptor; ECD, extracellular domain; GEFS+, generalized epilepsy with febrile seizures plus; Gly, glycine; M1-M4, transmembrane domains 1-4; PTX, picrotoxin History of human hyperekplexiaThe ability of strychnine to influence inhibitory reflexes and to convert these into excitatory reflexes was originally shown by Owen and Sherrington (1911). Hyperekplexia (Startle disease, Stiff baby syndrome, STHE -startle disease or hyperekplexia, OMIM 149400) was first described by Kirstein and Silfverskiold (1958) long before recombinant systems became available. In 1966 Suhren et al. reported a family with 25 members through five generations that suffered from abnormal severe startle reactions. This family was clinically described as having an autosomal dominant inheritance with an abnormal startle reaction in affected patients, which was elicited by different stimuli that did not provoking similar reactions in healthy controls. With the help of electroencephalographic (EEG) observations, a subcortical origin, for example, some midline structure like the brainstem, was proposed as being the source for this abnormal startle reaction. Furthermore, the patients were c...

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The Importance of TM3-4 Loop Subdomains for Functional Reconstitution of Glycine Receptors by Independent Domains

Cited by 14 publications

References 36 publications

New Hyperekplexia Mutations Provide Insight into Glycine Receptor Assembly, Trafficking, and Activation Mechanisms

New Hyperekplexia Mutations Provide Insight into Glycine Receptor Assembly, Trafficking, and Activation Mechanisms

Length of the TM3-4 loop of the glycine receptor modulates receptor desensitization

Glycine receptor mouse mutants: model systems for human hyperekplexia

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