UC Davis

Synaptic transmission is mediated by diverse ion channels and receptors and the fine regulation of those ion channels and receptors determines physiological functions in the brain. Thus, molecular mechanisms of function and regulation of them have been extensively studied to understand how neurons work.AMPA-type glutamate receptor (AMPAR) is responsible for the most fast excitatory transmission in the brain. Phosphorylation and surface insertion of AMPARs is essential for augmentation of long-term potentiation (LTP) which is the physiological correlate of learning and memory. AMPAR and β2 adrenergic receptor (β2AR) form functional supramolecular signaling complexes and stimulation of β2AR enhances phosphorylation and trafficking of AMPARs through GS protein, adenylyl cyclase (AC), and PKA signaling. PKA phosphorylates S845 in the C-terminus of GluA1 subunit. Phosphorylation at S845 augments AMPAR surface expression and postsynaptic targeting. The regulation of AMPARs could be influenced by ligands of β2ARs or AMPAR-interacting proteins. Chapter I will review fundamental understandings of synaptic transmission and plasticity and features of AMPARs in neurons. In chapter II, regulation of surface insertion of AMPARs by norepinephrine (NE), a ligand of β2AR, via intracellular β2AR – AC – PKA signaling will be examined. Also, the role of transporters for NE such as organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT) in stimulation of intracellular β2AR by NE will be investigated. The study in chapter III will suggest a novel mechanism of regulating trafficking of AMPARs through their association with L-type calcium channel, CaV1.2. In addition, the interaction between AMPAR and CaV1.2 will be characterized by biochemical experiments. In chapter IV, it will be discussed how this study contributes to the understanding of regulation of AMPARs and the development of therapeutics for neuronal disorders.