Local cyclic AMP signalling in synaptic plasticity. (360G-Wellcome-104194_Z_14_Z)

The second messenger cAMP can trigger long-term potentiation of synapses following electrical or hormonal stimulation. cAMP is elevated within different subcellular compartments, depending on the stimulus, where its primary intracellular receptor protein kinase A (PKA) is anchored in proximity to its substrates. I will investigate three poorly understood elements of local cAMP signalling. First, I will engineer synthetic PKA regulatory and catalytic subunits to enable identification of PKA subst rates and anchoring proteins associated with different forms of long-term potentiation. Second, using temporally-controlled crosslinking, I will test a novel hypothesis for explaining how different sub-neuronal populations of PKA are isolated from one another. Third, I will combine structural, biophysical and electrophysiological methods to determine how the AKAP79 postsynaptic complex coordinates local cAMP and calcium signals. The research will benefit from collaborations with proteomics exper ts in Zurich, and ion channel specialists at UCL. Taken together, this work will advance understanding of the molecular basis of synaptic plasticity, and generate technologies that can be applied in other biological systems including the heart. The research is relevant to disease as the synapse is a locus for pathological mutations, and modifying cyclic AMP signaling is a potential avenue for disease intervention.