Signaling Scaffolds for Specificity in Neuromodulator Action

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Abstract b2-adrenoceptor signaling is critical for adrenergic regulation of synaptic plasticity and neurodegeneration, and has been proposed to have therapeutic potentials for Alzheimer’s and Parkinson’s diseases. However, b- adrenoceptors (b-ARs) exhibit highly complicated pharmaceutical effects. This is exemplified by clinical results, in which b-AR drugs modulate receptor paralogs in different organs to elicit both therapeutic and clinically harmful effects at the same time. We aim to understand the signaling specificity of b2-adrenoceptors (b2-ARs), mechanisms through which they are selectively coupled to different intracellular signaling proteins and molecular effectors under different conditions. Our published and preliminary results manifest the signaling scaffold, synapse-associated protein of 97 kDa (SAP97) as an orchestrator of b2-AR signaling in hippocampal neurons. Specifically, the b-isoform of SAP97 (S97b) tethers b2-ARs and the effector voltage-gated potassium channel subunit Kv1.1 together to transduce activation of b2-AR signaling into inhibition of Kv1.1 and its removal from the dendrite surface (collectively referred to as Kv1.1 inhibition). Consequently, b2-AR-induced Kv1.1 inhibition increases dendritic excitability and lowers the induction threshold for long-term synaptic potentiation. Given b2-AR-signaling also regulates the phosphorylation of the AMPA receptor subunit GluA1, but through a different signaling scaffold, we hypothesize that signaling scaffolds mediate the signaling specificity and the interactions can be used as specific pharmacological targets. In this proposal, using the S97b/b2-AR/Kv1.1 complex as an exemplary model, we aim to gain mechanistic insights into a) how the diverse b2-AR signaling events are specifically regulated; b), what the molecular components of the S97b/b2-AR/Kv1.1 complex are to achieve signaling specificity; and c) what are the behavioral correlates of the S97b/b2-AR/Kv1.1 signaling pathway in mice. Importantly, in SAP97-lacking neurons, the signaling pathway governing b2-AR dependent dendritic excitability is impaired with a ~100% penetrance, allowing an analysis with minimal confounding effects of functional redundancy. The outcomes of our proposed experiments will provide a set of mechanistically clear drug targets for treating psychiatric, neurological, immunological or cardiovascular disorders, and perhaps more importantly lead to a novel and generalizable molecular scheme, through which G-protein-coupled receptors achieve biased and selective regulations of specific effector proteins to modulate synaptic transmission and plasticity.