Abstract
Schizophrenia is a common debilitating disease characterized by continuous or relapsing episodes of psychosis. Although the molecular mechanisms underlying this psychiatric illness remain incompletely understood, a growing body of clinical, pharmacological, and genetic evidence suggests that G protein-coupled receptors (GPCRs) play a critical role in disease development, progression, and treatment. This pivotal role is further highlighted by the fact that GPCRs are the most common targets for antipsychotic drugs. The GPCRs activation evokes slow synaptic transmission through several downstream pathways, many of them engaging intracellular Ca2+ mobilization. Dysfunctions of the neurotransmitter systems involving the action of GPCRs in the frontal and limbic-related regions are likely to underly the complex picture that includes the whole spectrum of positive and negative schizophrenia symptoms. Therefore, the progress in our understanding of GPCRs function in the control of brain cognitive functions is expected to open new avenues for selective drug development. In this paper, we review and synthesize the recent data regarding the contribution of neurotransmitter-GPCRs signaling to schizophrenia symptomology.
Highlights
Schizophrenia is one of the most severe psychiatric disorders with the onset typically observed in late-adolescence or early adulthood
We provide a summary of G protein-coupled receptors (GPCRs)-acting neurotransmitters and chemokines and their role in schizophrenia as well as discuss the treatment involving novel mechanisms of GPCR
Novel drugs targeting the allosteric binding site in Muscarinic acetylcholine receptors (mAChRs) helped to extend our knowledge about the role of these receptors in Ca2+ -dependent signal transduction in the brain and they turned out to be promising in the treatment of psychotic symptoms commonly observed in patients with schizophrenia
Summary
Schizophrenia is one of the most severe psychiatric disorders with the onset typically observed in late-adolescence or early adulthood. The main theory of schizophrenia was centered on dopamine and its D2 receptor This hypothesis is based on two types of observations: first, antipsychotic medications antagonized dopamine receptors and second, certain drugs such as amphetamine caused psychosis or exacerbated schizophrenic symptoms by enhancing dopamine activity in subcortical and limbic brain regions [5]. Comprehensive research on GPCR family led to the identification of several allosteric positive or negative modulators or functionally selective compounds targeting different neurotransmitter systems that are in the center of the concept of biased ligands, which modulate only a given receptor’s downstream signaling [15,16] The application of this GPCRs-based concept of schizophrenia treatment raises the possibility to implement therapeutically relevant outcomes with neglectable side effects. Calcineurin is linked to receptors for several brain transmitters including glutamate, dopamine, and GABA, and plays a key role in the interaction between pro-inflammatory and anti-inflammatory signals [26]
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