Modulation of AMPA receptor properties by auxiliar.. (MOAMAUX)
Modulation of AMPA receptor properties by auxiliary subunits
Start date: Jan 1, 2012,
End date: Dec 31, 2015
AMPA-type glutamate receptors (AMPARs) mediate most fast excitatory synaptic transmission in the brain. The regulation of certain AMPARs (calcium-permeable; CP-AMPARs) is relevant in synaptic plasticity, neuronal development and certain neurological diseases. AMPARs are regulated by transmembrane AMPA regulatory proteins (γ-2, -3, -4, -8; TARPs), which affect the trafficking and also important biophysical properties of AMPARs. Among them, we have recently demonstrated that TARPs increase single-channel conductance and attenuate block by intracellular polyamines of CP-AMPARs (Soto et al., 2007). However, the mechanisms involved in those changes are yet to be determined. On the other hand, new AMPARs auxiliary subunits have been recently discovered, such as γ-5, γ-7 or CNIHs raising interesting questions regarding the role of these proteins in AMPARs function. For example, how do TARPs modify the block of AMPARs by polyamines? How do the new auxiliary subunits affect some biophysical properties of AMPARs? Do TARPs or CNIHs modulate AMPARs in periferic nervous system (motorneurons or Schwann cells)? Therefore, the aim of the proposed research project is to further our understanding of the roles played by AMPARs auxiliary subunits (TARPs and CNIHs). We will address the following issues: 1) Using patch-clamp techniques we will investigate AMPARs modulation by auxiliary subunits and the molecular mechanisms involved in that modulation. 2) With the patch-clamp technique in either expression systems or neuronal cultures, we will study AMPARs auxiliary subunits focusing on the new recently discovered ones. We will take advantage of pharmacological and molecular tools (site-directed mutagenesis and siRNA) combined with the patch-clamp records. 3) The role of auxiliary subunits will be investigated in motor neurons and Schwann cells. We anticipate that the results will shed new light on the AMPAR field that will be invaluable in future improvements for certain CNS conditions.
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