Glutamate ionotropic receptor AMPA type subunit 1 pre-messenger RNA (GRIA1 pre-mRNA) (GRIA1 pre-mRNA)

The GRIA1 pre-mRNA at the splice sites flanking the GluA1-flip exon is a critical regulatory target for modulating the functional properties of AMPA-type glutamate receptors in the central nervous system. The GRIA1 gene encodes the GluA1 subunit, which undergoes alternative splicing of two mutually exclusive exons, termed 'flip' and 'flop,' located just before the fourth transmembrane domain (Sommer et al., 1990, Science). The flip isoform is characterized by slower desensitization and faster resensitization kinetics compared to the flop isoform, leading to higher steady-state currents and increased neuronal excitability (Penn et al., 2008, Journal of Neuroscience). Dysregulation of the GluA1 flip/flop ratio has been implicated in the pathophysiology of several neuropsychiatric disorders, including major depressive disorder, schizophrenia, and epilepsy (Gurevich et al., 2002, Neuropsychopharmacology). By utilizing splice-switching antisense oligonucleotides (SSOs) to target the splice sites flanking the flip exon, it is possible to therapeutically shift the splicing balance to restore normal glutamatergic signaling. This approach offers a high degree of specificity, potentially avoiding the side effects associated with broad-spectrum AMPA receptor agonists or antagonists by fine-tuning the receptor's kinetic profile rather than its total expression or activity.

Other names

GluA1 pre-mRNAGRIA1 flip/flop splice siteGlutamate receptor 1 pre-mRNAGluR1 pre-mRNA

Splice-switching antisense oligonucleotides bind to the pre-mRNA at the splice sites flanking the flip exon, sterically hindering the spliceosome to modulate the inclusion or exclusion of the exon and thereby altering the ratio of GluA1-flip to GluA1-flop protein isoforms.