Balanced Expression of G Protein-coupled Receptor Subtypes in the Mouse, Macaque, and Human Cerebral Cortex

G-coupled receptors (GPCRs) modulate brain function by signaling through heterotrimeric G(q/11), G(s), and G(i/o) protein subtypes. Researchers frequently study neuromodulation via these GPCR-subtypes on a 'cell-by-cell' basis. Although useful to explore a small number of interactions among neuromodulatory systems under controlled settings, this approach fails to account for a global organization of GPCRs in the brain. Furthermore, because multiple receptors and signal transduction pathways are present in single cells, neuromodulation is controlled by groups of GPCRs rather than by individual receptors. Using an integrative approach, the present study examined how large GPCR-subtype communities (ensembles) are expressed in different anatomical regions. Using the Allen Brain Atlas (http://www.brain-map.org/), we analyzed the mRNA expression energy of hundreds of GPCR-subtypes located in mouse, macaque, and human brains. We found that although there was a heterogeneous expression of GPCR-mRNA across all cortical regions, there were strong spatial correlations among congregated G(q/11)-, G(s)-, and G(i/o)-linked systems. Correlation strength increased with age but dropped when randomly removing genes from their corresponding groups. These findings suggest that the expression patterns of GPCR subtypes and receptor families are intricately intertwined. Well-orchestrated interactions by neuromodulatory-GPCR ensembles could be crucial for the brain to function as a highly integrated complex system. (C) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.