Insights into Nuclear G-Protein-Coupled Receptors as Therapeutic Targets in Non-Communicable Diseases

Abstract

G-protein-coupled receptors (GPCRs) comprise a large protein superfamily divided into six classes, rhodopsin-like (A), secretin receptor family (B), metabotropic glutamate (C), fungal mating pheromone receptors (D), cyclic AMP receptors (E) and frizzled (F). Until recently, GPCRs signaling was thought to emanate exclusively from the plasma membrane as a response to extracellular stimuli but several studies have challenged this view demonstrating that GPCRs can be present in intracellular localizations, including in the nuclei. A renewed interest in GPCR receptors’ superfamily emerged and intensive research occurred over recent decades, particularly regarding class A GPCRs, but some class B and C have also been explored. Nuclear GPCRs proved to be functional and capable of triggering identical and/or distinct signaling pathways associated with their counterparts on the cell surface bringing new insights into the relevance of nuclear GPCRs and highlighting the nucleus as an autonomous signaling organelle (triggered by GPCRs). Nuclear GPCRs are involved in physiological (namely cell proliferation, transcription, angiogenesis and survival) and disease processes (cancer, cardiovascular diseases, etc.). In this review we summarize emerging evidence on nuclear GPCRs expression/function (with some nuclear GPCRs evidencing atypical/disruptive signaling pathways) in non-communicable disease, thus, bringing nuclear GPCRs as targets to the forefront of debate.

TAAR1 Expression in Human Macrophages and Brain Tissue: A Potential Novel Facet of MS Neuroinflammation

“…Under standard conditions, resting macrophages showed TAAR1 protein expression primarily localized to the nucleus, with pro-inflammatory stimulation showing a shift to a diffuse intracellular distribution ( Figure 2 ), presumably cytoplasmic. Nuclear functions of GPCRs are an emerging area of therapeutic interest, with established functions in regulation of transcription, cell proliferation, cell migration, apoptosis, and angiogenesis [ 29 ]. With regards to TAAR1, nuclear sub-cellular distribution has previously been seen in some, but not all, breast cancer cell lines [ 26 ], although the functional relevance of this has yet to be determined.…”

Synergistic Interaction of 5-HT1B and 5-HT2B Receptors in Cytoplasmic Ca2+ Regulation in Human Umbilical Vein Endothelial Cells: Possible Involvement in Pathologies

“…Intracellular 5-HT 1B R is located predominantly in the nuclear region, while 5-HT 2B R is distributed rather evenly in the cells. Expression in the nuclear membrane has been shown for different G-protein-coupled receptors (GPCRs) [ 41 , 42 ]. Various nuclear receptors activate G-proteins and stimulate the formation of second messengers (cAMP, IP3, etc.).…”

Functional Characterization of Sugar Transporter CRT1 Reveals Differential Roles of Its C-Terminal Region in Sugar Transport and Cellulase Induction in Trichoderma reesei

“…One prominent example is G-protein coupled receptors (GPCRs) that are endocytosed to be relocated to the nucleus. This relocalization is found to be capable of triggering identical or distinct signaling pathways as their counterparts on cell surface ( 37 ). On the other hand, the endoplasmic reticulum (ER) Sec61 translocon has been reported to localize at the nuclear membrane and assist the intracellular translocation of the epidermal growth factor receptor (EGFR) into the nucleus ( 38 ).…”