| First Author | Schaefer N | Year | 2017 |
| Journal | J Neurosci | Volume | 37 |
| Issue | 33 | Pages | 7948-7961 |
| PubMed ID | 28724750 | Mgi Jnum | J:248717 |
| Mgi Id | MGI:6092912 | Doi | 10.1523/JNEUROSCI.0009-17.2017 |
| Citation | Schaefer N, et al. (2017) Disruption of a Structurally Important Extracellular Element in the Glycine Receptor Leads to Decreased Synaptic Integration and Signaling Resulting in Severe Startle Disease. J Neurosci 37(33):7948-7961 |
| abstractText | Functional impairments or trafficking defects of inhibitory glycine receptors (GlyRs) have been linked to human hyperekplexia/startle disease and autism spectrum disorders. We found that a lack of synaptic integration of GlyRs, together with disrupted receptor function, is responsible for a lethal startle phenotype in a novel spontaneous mouse mutant shaky, caused by a missense mutation, Q177K, located in the extracellular beta8-beta9 loop of the GlyR alpha1 subunit. Recently, structural data provided evidence that the flexibility of the beta8-beta9 loop is crucial for conformational transitions during opening and closing of the ion channel and represents a novel allosteric binding site in Cys-loop receptors. We identified the underlying neuropathological mechanisms in male and female shaky mice through a combination of protein biochemistry, immunocytochemistry, and both in vivo and in vitro electrophysiology. Increased expression of the mutant GlyR alpha1(Q177K) subunit in vivo was not sufficient to compensate for a decrease in synaptic integration of alpha1(Q177K)beta GlyRs. The remaining synaptic heteromeric alpha1(Q177K)beta GlyRs had decreased current amplitudes with significantly faster decay times. This functional disruption reveals an important role for the GlyR alpha1 subunit beta8-beta9 loop in initiating rearrangements within the extracellular-transmembrane GlyR interface and that this structural element is vital for inhibitory GlyR function, signaling, and synaptic clustering.SIGNIFICANCE STATEMENT GlyR dysfunction underlies neuromotor deficits in startle disease and autism spectrum disorders. We describe an extracellular GlyR alpha1 subunit mutation (Q177K) in a novel mouse startle disease mutant shaky Structural data suggest that during signal transduction, large transitions of the beta8-beta9 loop occur in response to neurotransmitter binding. Disruption of the beta8-beta9 loop by the Q177K mutation results in a disruption of hydrogen bonds between Q177 and the ligand-binding residue R65. Functionally, the Q177K change resulted in decreased current amplitudes, altered desensitization decay time constants, and reduced GlyR clustering and synaptic strength. The GlyR beta8-beta9 loop is therefore an essential regulator of conformational rearrangements during ion channel opening and closing. |
