Systems Pharmacology: Enabling Multidimensional Therapeutics

Maudsley, Stuart; Leysen, Hanne; Gastel, Jaana van; Martin, Bronwen

doi:10.1016/b978-0-12-820472-6.00017-7

Cited by 2 publications

(1 citation statement)

References 714 publications

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“…Emerging research has demonstrated that G protein-coupled receptor (GPCR) systems play an important, multidimensional role in the aging process [1][2][3][4][5][6][7][8][9]. GPCRs have long been characterized as controllers of cell-to-cell communication and thus the target of multiple therapeutic systems that control endocrine functionality in health and diseases [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process

Maudsley

Schrauwen

Harputluoğlu

et al. 2023

IJMS

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G protein-coupled receptors (GPCRs) play a significant role in controlling biological paradigms such as aging and aging-related disease. We have previously identified receptor signaling systems that are specifically associated with controlling molecular pathologies associated with the aging process. Here, we have identified a pseudo-orphan GPCR, G protein-coupled receptor 19 (GPR19), that is sensitive to many molecular aspects of the aging process. Through an in-depth molecular investigation process that involved proteomic, molecular biological, and advanced informatic experimentation, this study found that the functionality of GPR19 is specifically linked to sensory, protective, and remedial signaling systems associated with aging-related pathology. This study suggests that the activity of this receptor may play a role in mitigating the effects of aging-related pathology by promoting protective and remedial signaling systems. GPR19 expression variation demonstrates variability in the molecular activity in this larger process. At low expression levels in HEK293 cells, GPR19 expression regulates signaling paradigms linked with stress responses and metabolic responses to these. At higher expression levels, GPR19 expression co-regulates systems involved in sensing and repairing DNA damage, while at the highest levels of GPR19 expression, a functional link to processes of cellular senescence is seen. In this manner, GPR19 may function as a coordinator of aging-associated metabolic dysfunction, stress response, DNA integrity management, and eventual senescence.

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Section: Introductionmentioning

confidence: 99%

GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process

Maudsley

Schrauwen

Harputluoğlu

et al. 2023

IJMS

Self Cite

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GPCRs Are Optimal Regulators of Complex Biological Systems and Orchestrate the Interface between Health and Disease

Leysen

Walter

Christiaenssen

et al. 2021

IJMS

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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.

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Systems Pharmacology: Enabling Multidimensional Therapeutics

Cited by 2 publications

References 714 publications

GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process

GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process

GPCRs Are Optimal Regulators of Complex Biological Systems and Orchestrate the Interface between Health and Disease

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