Abstract
GPCRs arguably represent the most effective current therapeutic targets for a plethora of diseases. GPCRs also possess a pivotal role in the regulation of the physiological balance between healthy and pathological conditions; thus, their importance in systems biology cannot be underestimated. The molecular diversity of GPCR signaling systems is likely to be closely associated with disease-associated changes in organismal tissue complexity and compartmentalization, thus enabling a nuanced GPCR-based capacity to interdict multiple disease pathomechanisms at a systemic level. GPCRs have been long considered as controllers of communication between tissues and cells. This communication involves the ligand-mediated control of cell surface receptors that then direct their stimuli to impact cell physiology. Given the tremendous success of GPCRs as therapeutic targets, considerable focus has been placed on the ability of these therapeutics to modulate diseases by acting at cell surface receptors. In the past decade, however, attention has focused upon how stable multiprotein GPCR superstructures, termed receptorsomes, both at the cell surface membrane and in the intracellular domain dictate and condition long-term GPCR activities associated with the regulation of protein expression patterns, cellular stress responses and DNA integrity management. The ability of these receptorsomes (often in the absence of typical cell surface ligands) to control complex cellular activities implicates them as key controllers of the functional balance between health and disease. A greater understanding of this function of GPCRs is likely to significantly augment our ability to further employ these proteins in a multitude of diseases.
Highlights
Understanding how to regulate, using a multidimensional G protein-coupled receptors (GPCR)-based approach, and reverse the pathological loss of systemic homeostasis across the lifespan is vital to the future design pipeline of therapeutics that can act to suppress the generation of fully matured disease states [133]
We have discussed how, in addition to their role as cell surface sensors of soluble factors, subcellular functions of GPCRs associated with stress responses likely control the connectivity between classical cellular perturbations and the incipient molecular signatures of diseases
This concept suggests the presence of a novel form of a pharmacological system that represents a highly nuanced functional interface between healthy stress response networks and pathological disease-generating molecular signatures
Summary
It is reasonable to contend that the most therapeutically important molecular targets at the present time are the transmembrane heptahelical G protein-coupled receptors (GPCR). The active conformation is stabilized by agonist binding or by mutagenesis that can relieve intramolecular constraints [18,19,20,21,22,23] In this model, GPCRs transmit signals through their capacity to act as guanine nucleotide exchange factors for the heterotrimeric guanine nucleotide-binding proteins (G proteins) in response to stimulatory ligand binding. Initiates the dissociation of the heterotrimeric G protein from the GPCR, followed by the break-up of the G protein heterotrimer releasing free GTP-bound α and βγ subcomplexes These two signaling components can stimulate, inhibit or physically recruit multiple downstream signal transduction effectors, e.g., adenylyl cyclase (AC), phospholipase C (PLC), GPCR kinases (GRKs) or GRK-interacting proteins [29]. The heterotrimeric G protein can transmit information to the intracellular milieu about the qualitative and quantitative nature of a specific extracellular stimuli [30,31]
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