Flip and Flop: A Cell-Specific Functional Switch in Glutamate-Operated Channels of the CNS

TLDR

AMPA receptors in the CNS contain a flip/flop module preceding the fourth transmembrane domain that, through alternative splicing, confers distinct pharmacological and kinetic properties to glutamate‑evoked currents. Expression analysis shows that flip and flop isoforms exhibit distinct spatial patterns in rat hippocampus, revealing an alternative‑splicing–driven functional switch in glutamate receptors.

Abstract

In the central nervous system (CNS), the principal mediators of fast synaptic excitatory neurotransmission are L-glutamate-gated ion channels that are responsive to the glutamate agonist α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). In each member of a family of four abundant AMPA receptors, a small segment preceding the predicted fourth transmembrane region has been shown to exist in two versions with different amino acid sequences. These modules, designated "flip" and "flop," are encoded by adjacent exons of the receptor genes and impart different pharmacological and kinetic properties on currents evoked by L-glutamate or AMPA, but not those evoked by kainate. For each receptor, the alternatively spliced messenger RNAs show distinct expression patterns in rat brain, particularly in the CA1 and CA3 fields of the hippocampus. These results identify a switch in the molecular and functional properties of glutamate receptors operated by alternative splicing.