Publications by authors named "Signe M Lyngby"
Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug's molecular mechanism of operation at the serotonin 5-HT receptor (5-HTR), which features two properties: VTX acts differently on rodent and human 5-HTR, and VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, voltage-clamp fluorometry and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HTR and an agonist-bound-like state of human 5-HTR, in line with the functional profile of the drug.
View Article and Find Full Text PDFAMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1-GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally.
View Article and Find Full Text PDFArticle Synopsis
- GRIA1 encodes the GluA1 subunit of AMPA receptors, which are crucial for brain function as excitatory receptors for the neurotransmitter L-glutamate, with the gene variants potentially linked to neurodevelopmental disorders.
- Seven individuals with GRIA1 variants (both homozygous and heterozygous) were identified, showing a range of mutations that affect cognition and speech, particularly one recurrent variant found in three individuals.
- Functional studies indicate that these mutations severely disrupt AMPA receptor function, with additional animal models demonstrating related motor deficits and cognitive impairments.