Gi/o-Protein Coupled Receptors in the Aging Brain

Abstract

Cells translate extracellular signals to regulate processes such as differentiation, metabolism and proliferation, via transmembranar receptors. G protein-coupled receptors (GPCRs) belong to the largest family of transmembrane receptors, with over 800 members in the human species. Given the variety of key physiological functions regulated by GPCRs, these are main targets of existing drugs. During normal aging, alterations in the expression and activity of GPCRs have been observed. The central nervous system (CNS) is particularly affected by these alterations, which results in decreased brain functions, impaired neuroregeneration, and increased vulnerability to neuropathologies, such as Alzheimer’s and Parkinson diseases. GPCRs signal via heterotrimeric G proteins, such as G o , the most abundant heterotrimeric G protein in CNS. We here review age-induced effects of GPCR signaling via the G i/o subfamily at the CNS. During the aging process, a reduction in protein density is observed for almost half of the G i/o -coupled GPCRs, particularly in age-vulnerable regions such as the frontal cortex, hippocampus, substantia nigra and striatum. G i/o levels also tend to decrease with aging, particularly in regions such as the frontal cortex. Alterations in the expression and activity of GPCRs and coupled G proteins result from altered proteostasis, peroxidation of membranar lipids and age-associated neuronal degeneration and death, and have impact on aging hallmarks and age-related neuropathologies. Further, due to oligomerization of GPCRs at the membrane and their cooperative signaling, down-regulation of a specific G i/o -coupled GPCR may affect signaling and drug targeting of other types/subtypes of GPCRs with which it dimerizes. G i/o -coupled GPCRs receptorsomes are thus the focus of more effective therapeutic drugs aiming to prevent or revert the decline in brain functions and increased risk of neuropathologies at advanced ages.

Lamprey Parapinopsin (“UVLamP”): a Bistable UV‐Sensitive Optogenetic Switch for Ultrafast Control of GPCR Pathways

“…They are therefore gatekeepers of brain function by reducing neuronal excitability and keeping the brain in balance during emotion and arousal, contributing to neuronal plasticity during development, learning and memory formation. The main and modulatory transmitter systems such as glutamate, GABA, serotonin, dopamine, Ach, adrenaline and noradrenaline rely on negative feedback mechanisms using GPCRs coupling to the G i/o pathway and therefore represent major drug targets of the pharmaceutical industry . These pathways can now be controlled in a highly precise manner using parapinopsin.…”

Taming the Sentinels: Microbiome-Derived Metabolites and Polarization of T Cells

“…The Gi/o proteins, common partners for all three SCFA-activated GPCRs, are considered to be inhibitory for adenylate cyclase (AC) and potassium channels. Thus, downstream signal transduction after SCFA-associated GPCR activation leads to diminished activity of AC, which in consequence inhibits cyclic adenosine monophosphate (cAMP) synthesis [ 38 , 39 ]. Additionally, a component of the GPR43 signalosome (a G q/11 protein) stimulates phospholipase C (PKC), which in turns leads to diacylglycerol (DAG) and inositol trisphosphate (IP 3 ) production, resulting in the activation of PKC and calcium signaling [ 40 ].…”

Adenosine Metabolism in the Cerebral Cortex from Several Mice Models during Aging

“…Several GPCRs that can couple to the Gi/o subfamily are modified during aging. Among these receptors, adenosine A 1 receptors have a reduced turnover rate, lesser functional output, and reduced protein levels (reviewed in [ 40 ]). In contrast, adenosine A 2A receptors, which are coupled to the Gs subfamily, seem to be potentiated by aging, and their overfunction accelerates neurodegeneration processes [ 41 , 42 ].…”

“…Homeostatic functions, neuromodulation, and neuroprotection via adenosine receptors also decrease with age [ 13 , 40 , 43 ]. In addition, aging and neurodegenerative diseases, such as AD, are generally associated with reduced cAMP signaling in the brain compared to normal levels (reviewed in [ 44 ]).…”