Potential Utility of Biased GPCR Signaling for Treatment of Psychiatric Disorders

Abstract

Tremendous advances have been made recently in the identification of genes and signaling pathways associated with the risks for psychiatric disorders such as schizophrenia and bipolar disorder. However, there has been a marked reduction in the pipeline for the development of new psychiatric drugs worldwide, mainly due to the complex causes that underlie these disorders. G-protein coupled receptors (GPCRs) are the most common targets of antipsychotics such as quetiapine and aripiprazole, and play pivotal roles in controlling brain function by regulating multiple downstream signaling pathways. Progress in our understanding of GPCR signaling has opened new possibilities for selective drug development. A key finding has been provided by the concept of biased ligands, which modulate some, but not all, of a given receptor’s downstream signaling pathways. Application of this concept raises the possibility that the biased ligands can provide therapeutically desirable outcomes with fewer side effects. Instead, this application will require a detailed understanding of the mode of action of antipsychotics that drive distinct pharmacologies. We review our current understanding of the mechanistic bases for multiple signaling modes by antipsychotics and the potential of the biased modulators to treat mental disorders.

β‐Arrestin1 is involved in hepatocellular carcinoma metastasis via extracellular signal‐regulated kinase‐mediated epithelial–mesenchymal transition

“…G-protein-coupled receptors (GPCRs) are critical modulators in signal transduction and comprise the largest family of membrane proteins in the human genome, which play vital functions in physiological and pathological processes, including inflammation and carcinogenesis. 4,5 β-Arrestin1 (ARRB1), a member of the GPCR family, functions as a scaffold in many cases to transmit signals. 6,7 ARRB1-mediated signaling can lead to the activation of several pathways, such as mitogen-activated protein kinase (MAPK), tyrosine kinases, and the AKT pathway and has been found to inhibit apoptosis and increase the migration and invasion of cancer cells.…”

“…G‐protein‐coupled receptors (GPCRs) are critical modulators in signal transduction and comprise the largest family of membrane proteins in the human genome, which play vital functions in physiological and pathological processes, including inflammation and carcinogenesis 4,5 . β‐Arrestin1 (ARRB1), a member of the GPCR family, functions as a scaffold in many cases to transmit signals 6,7 .…”

Non-Functional Trace Amine-Associated Receptor 1 Variants in Patients With Mental Disorders

“…Additionally, RO5166017 oxazole ring also engages in a H-bond with T100, while the two oxygen atoms of T1AM interact with N268 and D287 through H-bonds (Cichero et al, 2013). Therefore, the three different ligands might stabilize different conformers, that in turn might lead to a different mode of activation, through either G-protein- or β-arrestin-dependent pathways, and eventually scaffold distinct downstream signaling molecules, such as kinases and phosphatases (Komatsu et al, 2019). A more complex picture may derive from the interrelation between TAAR1 and other GPCRs (Braunig et al, 2018; Kohrle and Biebermann, 2019).…”

Using iPSC Models to Understand the Role of Estrogen in Neuron–Glia Interactions in Schizophrenia and Bipolar Disorder

“…Mental disorders are debilitating complex diseases, characterized by highly heterogeneous alterations in mood and behavioral traits, usually arising early in life in affected individuals [1,2]. The etiology of these disorders is complex and remains largely unexplained, hampering the development of preventive or curative treatments [3]. Schizophrenia (SCZ) predominantly affects perception, thoughts, and cognition, whereas bipolar disorder (BIP) mainly affects mood; however, there is a large degree of overlap in clinical characteristics and psychopharmacological treatment.…”