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.
G protein‐coupled receptors (GPCRs) are successful drug targets due to their functional involvement in nearly every biological process. GPCRs can generate functional signals via both G proteins and β‐arrestins. Our research has demonstrated that an additional non‐G protein signaling function may exist for GPCRs, i.e. the GIT2 (GRK interacting transcript 2) signaling pathway. The structural bases of differential signaling paradigm control in GPCRs are still relatively unclear. Through structural modification of conserved structural motifs in GPCRs, we have sought to unravel this conundrum. The hydrogen‐bond network, including transmembrane helix 1 (TM1) Asparagine (N1.50), TM2 Aspartate (D2.50), and TM7 Asparagine (N7.49), is conserved across the majority of Rhodopsin‐like GPCRs and is known to affect GPCR signal initiation. Human GPR19 however possesses a natural variation in this network, i.e. a Lysine substitution for the TM7 Asparagine N7.49. Here we have introduced selective point mutations to several of these conserved sites and have investigated how these changes affect G protein, β‐arrestin, and GIT2 signaling bias effects. We have investigated both the proteomic cellular response to expression level variation of wild type (WT) and mutant (MT) GPR19 forms, as well as the physical interactome of WT and MT forms by using quantitative mass spectrometry. With these data we have performed targeted bioinformatic analyses to investigate signaling bias effects at GPR19. Our results have demonstrated that the TM2 MT D2.50A was able to indeed shift signaling bias from β‐arrestin paradigms to GIT2 signaling paradigms. Our research, as well as others, have shown that β‐arrestin and GIT2 signaling can act in an opposite manner regarding stress resistance and DNA damage (both drivers of aging and age‐related disease), with the former facilitating damage and the latter attenuating damage. Controlling the ability of a GPCR to selectively regulate these pathways could show beneficial effects concerning DNA damage in the context of aging and age‐related disease.
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