||PICK1 (protein interacting with C-kinase 1) is a peripheral membrane protein that is known for its role in regulating membrane protein trafficking. The PDZ domain of PICK1 interacts with the intracellular C-terminal tails of cargo proteins while the BAR domain binds to lipid membranes. In the brain, PICK1 mainly regulates AMPA receptor synaptic trafficking which is an important mechanism for synaptic plasticity. In the first part of my study, we identified ICA69 (Islet cell autoantigen 69kD) as the major binding partner of PICK1. PICK1 and ICA69 form tight heteromeric BAR domain complexes and co-express in different tissues and at various developmental stages. In neurons, ICA69 co-localizes well with PICK1 in cell bodies and dendrites, but not synapses. Furthermore, overexpression of ICA69 redistributes PICK1 from synapses to dendrites, disrupts the PICK1-induced clustering of AMPA receptors and reduces synaptic targeting and surface expression of AMPA receptors by preventing formation of PICK1 homomeric complexes. The second part of my study focused on the novel function PICK1 and ICA69 in insulin secretion. Insulin is a key regulator for glucose homeostasis. However, the molecular machinery responsible for insulin granules trafficking and maturation are not clear. Here we reported that PICK1-ICA69 complexes associate with insulin granules at different maturation stages by switching ICA69- PICK1 heteromeric complexes to PICK1-PICK1 homomeric complexes. The double deficiency of PICK1 and ICA69 in mice leads to increased food and water intakes but lower body weight. These mice also show impaired glucose tolerance due to insufficient insulin secretion. Taken together, our results suggest that PICK1 and ICA69 are key factors for both AMPA receptor trafficking and insulin secretion. The conversion from ICA69-PICK1 heteromeric complexes to PICK1-PICK1 homomeric complexes could be an important mechanism for regulating these two processes.