Regulation of neuronal GPCR/PKA signaling by RBM12

Duke University, Durham NC

Investigators

Abstract

PROJECT SUMMARY G protein-coupled receptors (GPCRs) shape neuronal function in response to various neuromodulators and neurotransmitters. Conversely, dysregulation of their signaling pathways has been linked to neurological and neurodevelopmental disorders. This highlights the physiological significance of these cascades and the pressing need to better understand their cellular regulation. Here, we focus on RNA binding motif protein 12 (RBM12), a novel mediator of neuronal GPCR signaling that we identified through a functional genomic screen for regulators of the pathway. RBM12 is a poorly understood and understudied factor genetically linked to neurodevelopmental and neuropsychiatric disorders. This proposal will build on preliminary data demonstrating that RBM12 is a repressor of GPCR/cAMP/PKA signaling and test the central model that RBM12 is an RNA-binding protein that regulates GPCR signaling post-transcriptionally. We will apply complementary RNA genomics, biochemistry, cell signaling, and electrophysiology assays in human induced pluripotent stem cell-derived neurons in order to 1) define the mechanisms governing the RBM12-dependent regulation of neuronal GPCR signaling, 2) delineate the RBM12 sequence features that underlie the regulation and determine whether these are disrupted by disease-associated human polymorphisms, and 3) characterize the role of the RBM12-GPCR interplay in shaping neuronal activity. Successful completion of the studies will yield an integrated mechanistic and functional understanding of RBM12’s role in receptor-dependent neuronal function. Additionally, our analyses could pave the way for in vivo characterization of this interplay to establish RBM12-dependent dysregulation of GPCR/PKA cascades as a tentative novel mechanism underlying neuronal disorders associated with rare human mutations in that gene.