Abstract
G protein coupled receptors (GPCRs) were first characterized as signal transducers that elicit downstream effects through modulation of guanine (G) nucleotide-binding proteins. The pharmacotherapeutic exploitation of this signaling paradigm has created a drug-based field covering nearly 50% of the current pharmacopeia. Since the groundbreaking discoveries of the late 1990s to the present day, it is now clear however that GPCRs can also generate productive signaling cascades through the modulation of β-arrestin functionality. β-Arrestins were first thought to only regulate receptor desensitization and internalization – exemplified by the action of visual arrestin with respect to rhodopsin desensitization. Nearly 20 years ago, it was found that rather than controlling GPCR signal termination, productive β-arrestin dependent GPCR signaling paradigms were highly dependent on multi-protein complex formation and generated long-lasting cellular effects, in contrast to G protein signaling which is transient and functions through soluble second messenger systems. β-Arrestin signaling was then first shown to activate mitogen activated protein kinase signaling in a G protein-independent manner and eventually initiate protein transcription – thus controlling expression patterns of downstream proteins. While the possibility of developing β-arrestin biased or functionally selective ligands is now being investigated, no additional research has been performed on its possible contextual specificity in treating age-related disorders. The ability of β-arrestin-dependent signaling to control complex and multidimensional protein expression patterns makes this therapeutic strategy feasible, as treating complex age-related disorders will likely require therapeutics that can exert network-level efficacy profiles. It is our understanding that therapeutically targeting G protein-independent effectors such as β-arrestin will aid in the development of precision medicines with tailored efficacy profiles for disease/age-specific contextualities.
Highlights
The β-arrestin family comprises four members: visual arrestins and the non-visual arrestins (β-arrestin1 and β-arrestin2, referred to as arrestin2 and arrestin3, respectively)
To generate the most comprehensive LSI-based appreciation of gene-keyword associations we used a broad range of synonyms to extract the most amount of Gene Symbol data. Using this range of input terms (Aging, Ageing, Senescence, Senescent, Elderly, Elder, Longevity) we found that, using the cumulated Cosine Similarity scores for the interactome proteins associated with these input gerontological concept terms, for the majority of the terms (Aging, Ageing, Senescence, Senescent, and Longevity) a greater total association of the βarrestin2 interactome proteins with these concepts was observed compared to the βarrestin1 interactomes (Figure 3 and Supplementary Table S3)
Campo and co-workers recently demonstrated that the anti-inflammatory action of β-arrestin2 appears to be mediated partially through the direct inhibition of p38 mitogen activated protein kinase (MAPK) which prevents the activation of nuclear factor κB (NF-κB), and partially through cyclic adenosine monophosphate (cAMP) and PKA activation through G protein signaling, which exerts an inhibitory effect on NF-κB (Campo et al, 2015)
Summary
The β-arrestin family comprises four members: visual arrestins (arrestin1 and arrestin4) and the non-visual arrestins (β-arrestin1 and β-arrestin2, referred to as arrestin2 and arrestin3, respectively). Through the recruitment of these kinases to GPCRs after agonist-binding, β-arrestins grant distinct signaling activities upon the receptor – discriminating them physically from G protein-dependent functional GPCR forms (Luttrell and Lefkowitz, 2002).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
