Title : Subunit-selective N-terminal domain associations organize the formation of
AMPA receptor heteromers
Abstract :
- The assembly of AMPA-type glutamate receptors ( AMPARs ) into distinct ion channel tetramers ultimately governs the nature of information transfer at excitatory synapses
- How cells regulate the formation of diverse homo- and heteromeric AMPARs is unknown
- Using a sensitive biophysical approach, we show that the extracellular, membrane-distal AMPAR N-terminal domains (NTDs) orchestrate selective routes of heteromeric assembly via a surprisingly wide spectrum of subunit-specific association affinities
- Heteromerization is dominant, occurs at the level of the dimer, and results in a preferential incorporation of the functionally critical GluA2 subunit
- Using a combination of structure-guided mutagenesis and electrophysiology, we further map evolutionarily variable hotspots in the NTD dimer interface, which modulate heteromerization capacity
- This 'flexibility' of the NTD not only explains why heteromers predominate but also how GluA2-lacking, Ca(2 +)-permeable homomers could form, which are induced under specific physiological and pathological conditions
- Our findings reveal that distinct NTD properties set the stage for the biogenesis of functionally diverse pools of homo- and heteromeric AMPAR tetramers
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