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The Effects of Hyperekplexia-Causing Mutations on Desensitization and Oligomerization of Glycine Receptors
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The Effects of Hyperekplexia-Causing Mutations on Desensitization and Oligomerization of Glycine Receptors
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Dissertation
The Effects of Hyperekplexia-Causing Mutations on Desensitization and Oligomerization of Glycine Receptors
2019
Overview
Hyperekplexia “startle disease” is a neurological disorder that is primarily caused by hereditary mutations disrupting the inhibitory signals in the spinal cord. The Glycine receptor, GlyR, α-subunit GLRA1 gene is the main site of these mutations. As a result, GlyR loses its function of chloride channel due to decreased sensitivity to glycine, reduced surface expression, decreased current, or fast channel closure. The V280M mutation in GlyR-α1 subunit causes hyperekplexia but, surprisingly, these receptors showed a gain of function. The mutation produced spontaneous channel activity, increased glycine sensitivity, with no apparent reduction in the membrane expression. We investigated possible mechanisms for V280M α1GlyR in causing hyperekplexia. We took two approaches. Using electrophysiology, we found that the increased sensitivity of the receptor to glycine led to increased occupancy of the desensitized state. We conditioned α1GlyR with low concentrations of glycine, followed by activating the receptors by a saturating concentration of glycine. We found that 10µM glycine, the concentration present in cerebrospinal fluid (CSF), desensitized > 98% V280M α1GlyR compared to 30% of wild type α1GlyR. Using Number and Brightness imaging of SNAP-tagged GlyR; we monitored receptor oligomerization and receptor association with the anchoring protein gephyrin to form clusters. V280M α1GlyR formed larger oligomers than did wild type α1GlyR. However, V280M α1GlyR harboring gephyrin binding domain did not form clusters when associated with gephyrin, unlike wild type α1GlyR harbor gephyrin binding domain formed clusters when coexpressed with gephyrin. In conclusion, although V280M α1GlyR displays a gain of function, exposure of V280M α1GlyR to CSF levels of glycine would desensitize most of the receptors between synaptic signaling. Furthermore, V280M α1GlyR did not form clusters when associated with gephyrin, suggesting that V280M α1GlyR might fail to localize at the synapse.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9781392463604, 1392463602
