Abstract In the central nervous system (CNS), beta adrenergic receptors (BARs) are broadly expressed responding to norepinephrine (NE) signaling from projections from the Locus Coeruleus. NE regulates attention, arousal, and acuity as well as fear learning in health and is implicated in neurodegenerative disorders. Beta2 adrenergic receptors (B2ARs) are involved in long term potentiation through Gs-mediated activation of protein kinase A (PKA) regulating calcium channels and AMPA receptors. In addition to G-protein signaling activities, the B2AR itself can be modified affecting downstream signaling, including precise spatiotemporal regulation of signals in highly differentiated neurons. Little is known about the impacts these phosphorylation events have on NE- mediated receptor signaling and behavioral phenotypes. This dissertation research addresses this knowledge gap, examining signaling mechanisms of B2AR phosphorylation, the signaling and behavioral consequences of those phosphorylation events, and examines the role these phosphorylation events play in Parkinson’s disease (PD). Recently our lab found functionally distinct and selectively phosphorylated subpopulations of B2ARs exist in single neurons. These B2AR subpopulations are selectively phosphorylated at either a PKA (S261/262) or G-protein receptor kinase (GRK) (S355/356) site on the c-terminus of the receptor. Preliminary data show that GRK phosphorylation is necessary to promote signaling to the nucleus and gene expression, and also demonstrated that GRK-mediated B2AR signaling is protective against toxin mediated nigral neuron death in a model of PD. These data indicate that distinct subpopulations of B2AR are involved in multiple forms of learning and memory and disease processes. In this proposal, we hypothesize that GRK-mediated phosphorylation of B2AR controls the signaling mechanism by which B2AR promotes gene expression involved in memory and learning in health and is neuroprotective against toxin induced neuronal death in a PD model. Data and skills developed in this proposal will form the foundation of postdoctoral research examining B2AR signaling in Alzheimer’s disease.

Narrative Adrenaline-like chemicals in the brain contributes to alertness, fear responses, learning and memory, and are implicated in the pathogenesis of several neurodegenerative disorders. This project aims to examine how these chemicals in the central nervous system regulate gene expression and activity in neurons in health and disease.