UC Davis

Synapses and dendrites are functional units of information transmission, processing, and storage in neuronal circuits, whose structure and function are critical for proper cognition. They require a precisely organized assembly of proteins in which crucial interactions depend on the exact spatial alignment of the proteins. In neurons, tightly regulated Ca2+ is essential for neurotransmitter release, synaptic plasticity, and activity-induced gene transcription. Moreover, the neuromodulator norepinephrine (NE), which is crucial for arousal, attention, and memory, works to tune one’s focus and one’s neurons to highly relevant stimuli and information for optimal cognition. NE is the endogenous agonist of neuronal 2 adrenergic receptor (β2AR), which exists in distinct signaling complexes with the L-type calcium channel (LTCC) Cav1.2 and the AMPA receptor (AMPAR) subunit GluA1. The β2AR -Cav1.2 and β2AR-GluA1 signaling complexes are necessary for a particular form of synaptic plasticity, and previous work from the Hell lab has shown NE stimulates AMPAR surface insertion that is blocked by application of an LTCC antagonist. In chapter 1, I review the current knowledge about NE, the LTCC Cav1.2, the AMPAR and their functional coupling in the central nervous system. In chapter 2, I present data indicating differential regulation in Cav1.2 and GluA1 phosphorylation in the frontal cortex in vivo and the behavioral phenotypes of these phosphorylation sites. In chapter 3, I show circadian changes in phosphorylation of Cav1.2 and GluA1. In chapter 4, I examine the protein-protein interaction of Cav1.2 and GluA1. Lastly, in chapter 5, I discuss how my results contribute to the understanding of how phosphorylation and coupling of Cav1.2 and GluA1 play a role in function and dysfunction of the central nervous system.