Kurzfassung

Neurons in the brain alter their responsiveness to signals from other neurons, amechanism that underlies the fundamental processes of information transfer, learning,and memory. Synaptic transmission in most excitatory synapses is mediated byglutamate receptors of the AMPA type. Changes in responsiveness can be achievedby activity-driven alterations in AMPA receptor (AMPAR) subunit number,composition, and by posttranscriptional or posttranslational modifications such asphosphorylation,... Neurons in the brain alter their responsiveness to signals from other neurons, a mechanism that underlies the fundamental processes of information transfer, learning, and memory. Synaptic transmission in most excitatory synapses is mediated by glutamate receptors of the AMPA type. Changes in responsiveness can be achieved by activity-driven alterations in AMPA receptor (AMPAR) subunit number, composition, and by posttranscriptional or posttranslational modifications such as phosphorylation, glycosylation, or palmitoylation. The discovery that auxiliary AMPA receptor subunits affect receptor functions revealed even greater capacity for variation in receptor regulation. AMPA receptor auxiliary proteins influence the expression and function of AMPARs by a direct interaction. We recently discovered a novel family of AMPAR auxiliary proteins, namely the family of Cystine-knot AMPA receptor modulating proteins (CKAMPs, von Engelhardt et al. Science 2010; Khodosevich et al., Neuron 2014; Farrow et al., ELife 2015). The four members of this protein family (CKAMP39, CKAMP44, CKAMP52 and CKAMP59) exert very diverse influences on AMPARs properties and display different brain-region specific expression profiles. We and other showed with the help of knockout mice that CKAMP44 and CKAMP52 influence AMPAR function in the hippocampus. However, nothing is known about the functional role of the two other auxiliary proteins CKAMP39 and CKAMP59. Moreover, the structural properties of CKAMP family members underlying the influence on AMPARs have yet to be investigated. The goal of the proposed project is to investigate with the function of CKAMP family members in different brain areas with the help of conditional knockout mice and the structure of AMPAR/CKAMP complexes via X-ray crystallography/CryoEM. Data of this study will be important for all research fields on glutamatergic neurotransmission in pathological and non-pathological condition» weiterlesen» einklappen