Activator of G‐protein Signaling 3 null mice II: Exploring the functional roles of AGS3 in the immune system

Activator of G‐protein Signaling 3 (AGS3/Gpsm1), via regulation of G‐protein signaling, plays central functional roles in cell division, synaptic plasticity, addictive behavior and/or neuronal development. In addition to its expression in the CNS, AGS3 is also expressed in peripheral tissues and lymphoid organs such as spleen and thymus as well as in bone marrow‐derived dendritic cells (BMDCs). AGS3 expression is upregulated in B cells stimulated with LPS or anti‐IgM, in T cells stimulated with anti‐CD3 and IL‐2 and in BMDCs stimulated with LPS. As part of a broad effort to define the extent of functional diversity of AGS regulated‐events in vivo, we generated AGS3 null mice. Defects in Gαi signaling effect lymphocyte differentiation as well as some humoral responses to antigens; therefore, we measured lymphocyte populations and serum Ig levels as well as chemokine‐directed chemotaxis of lymphocytes and BMDCs from wild‐type and AGS3 (Gpsm1)‐null mice. Using a BRET‐based system to monitor AGS3‐Gαi interactions we observed CXCL12‐mediated regulation of AGS3‐RLuc – Gαi1‐YFP BRET as well as Gαi1‐dependent BRET between AGS3‐RLuc and CXCR4‐Venus, suggesting a role for AGS3‐Gαi in the integration of signals from chemokine receptors. These studies expand the functional repertoire for AGS3 and other GPR proteins in the immune system providing unexpected venues for the potential development of therapeutic agents.