GPCRs in Intracellular Compartments: New Targets for Drug Discovery

Abstract

The architecture of eukaryotic cells is defined by extensive membrane-delimited compartments, which entails separate metabolic processes that would otherwise interfere with each other, leading to functional differences between cells. G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors, and their signal transduction is traditionally viewed as a chain of events initiated from the plasma membrane. Furthermore, their intracellular trafficking, internalization, and recycling were considered only to regulate receptor desensitization and cell surface expression. On the contrary, accumulating data strongly suggest that GPCRs also signal from intracellular compartments. GPCRs localize in the membranes of endosomes, nucleus, Golgi and endoplasmic reticulum apparatuses, mitochondria, and cell division compartments. Importantly, from these sites they have shown to orchestrate multiple signals that regulate different cell pathways. In this review, we summarize the current knowledge of this fascinating phenomenon, explaining how GPCRs reach the intracellular sites, are stimulated by the endogenous ligands, and their potential physiological/pathophysiological roles. Finally, we illustrate several mechanisms involved in the modulation of the compartmentalized GPCR signaling by drugs and endogenous ligands. Understanding how GPCR signaling compartmentalization is regulated will provide a unique opportunity to develop novel pharmaceutical approaches to target GPCRs and potentially lead the way towards new therapeutic approaches.

The multimodal action of G alpha q in coordinating growth and homeostasis in theDrosophilawing imaginal disc

“…The copyright holder for this preprint this version posted January 9, 2023. ; https://doi.org/10.1101/2023.01.08.523049 doi: bioRxiv preprint Moreover, studies are needed to clarify the subcellular location and functional activity of Gαq and related GPCRs. Recently, GPCRs have been found to be active not only in the outer cell membrane but associated with the inner membranes of organelles within the cell [144], [145]. Also, further investigation is needed to map out key molecular players activating Gαq-mediated ICWs in vivo.…”

G Protein-Biased Agonists for Intracellular Angiotensin Receptors Promote Collagen Secretion in Myofibroblasts

“…In other GPCR systems, for example, the intracellular β-adrenergic receptors that rely on a catecholamine transporter (OCT3) for ligand translocation into the intracellular compartment, it is possible to interrogate the intracellular signaling pathways by blocking or knocking out the transporter. − However, this approach is not applicable to the angiotensinergic system, as Ang II does not use a molecular transporter, and selectively knocking intracellular receptor counterparts out or down is not feasible with the current technologies available. As reviewed by Fasciani and colleagues, responses originating from compartmentalized GPCRs can be distinguished from those evoked by their cell surface counterparts using small molecules with contrasting lipophilicities whenever these drugs are available (as is the case for pergolide, a highly lipophilic nonselective dopamine agonist, compared to poorly cell-permeable dopamine). Linear peptides, such as Ang II and related analogues, face limitations in cell permeability due to their size and charge.…”

Computational Peptide Design Cotargeting Glucagon and Glucagon-like Peptide-1 Receptors

“…The extracellular domain (ECD), ECLs, and terminals of receptors were modeled using Robetta () which is a protein structure prediction tool and Modeller9.17 . The ECD of receptors was modeled along with the signal sequence, which ideally represents a nascent GPCR case . The signal peptide is normally cleaved off from the mature protein .…”