Project Details
Projekt
Life cycle of AMPA receptors under acute metabolic stress
Applicant
Dr. Nadine Erlenhardt
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular and Cellular Neurology and Neuropathology
Molecular and Cellular Neurology and Neuropathology
Term
from 2018 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 394431587
AMPA-type glutamate receptors (AMPARs) mediate most of the fast excitatory neurotransmission in the mammalian brain providing a major route of sodium influx into the postsynaptic spine. The amount of sodium entering the spine and the excitability of the postsynaptic cell largely depend on the amount of AMPARs in the postsynaptic membrane as well as their biophysical properties. Trafficking and gating of AMPARs is determined by their molecular composition. AMPARs consist as heterotetramers of the pore-forming and glutamate binding subunits GluA1-4 and a variety of auxiliary subunits leading to a wide range of gating kinetics and subcellular processing.AMPARs play an important part in the pathophysiology of metabolic failure. In the late phase following metabolic stress they show subunit-dependent alterations in subcellular trafficking behavior resulting in a switch from GluA2-containing Ca2+-impermeable to GluA2-lacking Ca2+-permeable AMPARs in the postsynaptic membrane. This subunit switch leads to an increase in EPSC amplitudes and to an influx of calcium and zinc into the postsynaptic neuron, finally resulting in excitotoxicity and delayed cell death. However, the role of AMPARs in the first hour following metabolic stress has hardly been investigated.Here, we intend to investigate the postsynaptic signaling of AMPARs in response to inhibition of cellular metabolism. We will particularly focus on the regulatory mechanisms of AMPAR auxiliary subunits. We will apply a multidisciplinary approach combining biochemical, cell and molecular biological and electrophysiological techniques in order to unravel the mechanisms underlying re-organization of postsynaptic AMPAR complexes and the functional consequences for the postsynaptic neuron in the early phase of metabolic stress.
DFG Programme
Research Units
