RBM12 is a high-penetrance risk factor for familial schizophrenia and psychosis, yet its precise cellular functions and the pathways to which it belongs are not known. We utilize two complementary models, HEK293 cells and human iPSC-derived neurons, and delineate RBM12 as a novel repressor of the G protein-coupled receptor/cyclic AMP/protein kinase A (GPCR/cAMP/PKA) signaling axis. We establish that loss of RBM12 leads to hyperactive cAMP production and increased PKA activity as well as altered neuronal transcriptional responses to GPCR stimulation. Notably, the cAMP and transcriptional signaling steps are subject to discrete RBM12-dependent regulation. We further demonstrate that the two RBM12 truncating variants linked to familial psychosis impact this interplay, as the mutants fail to rescue GPCR/cAMP signaling hyperactivity in cells depleted of RBM12. Lastly, we present a mechanism underlying the impaired signaling phenotypes. In agreement with its activity as an RNA-binding protein, loss of RBM12 leads to altered gene expression, including that of multiple effectors of established significance within the receptor pathway. Specifically, the abundance of adenylyl cyclases, phosphodiesterase isoforms, and PKA regulatory and catalytic subunits is impacted by RBM12 depletion. We note that these expression changes are fully consistent with the entire gamut of hyperactive signaling outputs. In summary, the current study identifies a previously unappreciated role for RBM12 in the context of the GPCR/cAMP pathway that could be explored further as a tentative molecular mechanism underlying the functions of this factor in neuronal physiology and pathophysiology.

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G‐protein coupled receptors (GPCRs) are pivotal to neuronal functions such as neurotransmission and memory formation, and aberrant GPCR signaling has been implicated in complex neuropsychiatric disorders. Our ability to develop efficient therapeutic strategies therefore hinges on better understanding of the molecular factors that govern GPCR activity. Upon activation, GPCRs modulate a myriad of downstream second messengers and molecules that generate cellular responses, including the transcription of cAMP‐dependent target genes. Through a genome‐wide CRISPR‐based screen with a fluorescent cAMP transcriptional reporter, we identified RNA‐binding motif 12 (Rbm12) as a novel potent repressor of the GPCR/cAMP pathway. While Rbm12 is a genetic risk factor for familial psychosis, its precise cellular functions are unknown. We hypothesize that the loss of Rbm12’s regulation of the GPCR/cAMP pathway contributes to the development of psychosis. To investigate this intriguing possibility, we performed CRISPR‐based gene editing to show that Rbm12 deficiency leads to increased cAMP accumulation and hyperactivation of multiple cAMP‐dependent target genes downstream of several key neurotransmitter GPCRs. The signaling hyperactivation caused by Rbm12 loss is similarly conserved in human induced pluripotent stem cell‐derived neurons. Furthermore, we demonstrate that disease‐linked truncating mutations in Rbm12 (c.2377G>T and c.2532delT) fail to rescue the signaling hyperactivation due to possible loss‐of‐function and protein instability, respectively. Together, these experiments provide critical insights into this uncharacterized gene. By uncovering the novel regulatory role of a neuropsychiatric disease risk gene in GPCR signaling, we expand our understanding of the molecular basis of complex neurobiological disorders and enable the identification of novel druggable targets.