How does camp modulate glua3-containing receptors?
Narges Baghi, Armagan Kocer*
Bioelectric signaling and engineering (BioEE), Faculty of Science and Technology (TNW), University of Twente, Enschede, The Netherlands,
Abstract
AMPA receptors are ligand-gated ion channels acvated by the neurotransmiter glutamate released from the presynapc neuron. These receptors consist of four subunits, GluA1–GluA4, in the form of dimers of dimers.
Recent in vivo studies conducted on Purkinje cells have shown that GluA2/A3 receptors exhibit disnct paterns of synapc plascity in the presence of intracellular cyclic AMP (cAMP). In this unique cAMP-dependent GluA3-mediated synapc plascity mechanism, long-term potenaon (LTP) is not dependent on the trafficking of more GluA1 into the post-synapc membrane but rather on the open-channel probability and conductance of GluA3 receptors
Our research aims to elucidate the molecular mechanism of the new LTP, which depends on the changes in the open channel probability and conductance of GluA3-containing receptors instead of their trafficking into the post-synaptic area in the presence of cAMP.
Sequential alignment of GluA1, 2, and 3 subunits indicated a notable difference between GluA3 and GluA1 subunit sequences; there was a proline-rich region in the first intracellular loop 1 in GluA3 subunit, which was absent in the GluA1. In biological systems, PRR is involved in quick signaling through protein-protein interactions. We hypothesized that the PRR of the GluA3 subunit is responsible for the new LTP mechanism in GluA3-containing AMPARs.
To test this hypothesis, we first developed a functional assay in a heterologous system using HEK cells and showed the activity of the receptors. Then, we generated chimeric receptors between GluA1 and GluA3 by swapping the first intracellular loop of GluA1 with GluA3, which has the PRR sequence. And showed the role of PRR in the new LTP mechanism.