β-Arrestin Based Receptor Signaling Paradigms: Potential Therapeutic Targets for Complex Age-Related Disorders

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.

Subcellular hot spots of GPCR signaling promote vascular inflammation

“…β-arrestins regulate GPCR-stimulated NFκB activity in various cell types [ 20 ]; however, new work suggests that the major driver of NFκB activation utilized by GPCRs is the caspase recruitment domain–containing proteins known as CARMA. CARMA associates with two signaling proteins B-cell lymphoma protein 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) ( Figure 2 ).…”

Signal Transduction Profiling of Angiotensin II Type 1 Receptor With Mutations Associated to Atrial Fibrillation in Humans

“…For example, WNK isoforms, Src and Src-related kinases, AMPK, GSK3/Akt pathway, among others, showed a different phosphorylation profile induced by the analyzed mutations, when compared to WT AT1R. All of them have been described to be involved on different cardiovascular dysfunctions, fibrosis and atrial fibrillation ( Penela et al, 2001 ; Fessart et al, 2005 ; Kim et al, 2005 ; Gavi et al, 2006 ; Kraja et al, 2011 ; Harada et al, 2015 ; Qi et al, 2017 ; Van Gastel et al, 2018 ), thus these signaling pathways could also be contribute to the AF phenotype induced by the studied AT1 mutations.…”

Involvement of ACE2/Ang-(1-7)/MAS1 Axis in the Regulation of Ovarian Function in Mammals

“…It is well known that β-arrestins are involved in the desensitization, internalization, and recycling of G protein-coupled receptors (GPCRs). However, the latest research indicates that these multifunctional adapter proteins not only mediate the inhibition of GPCRs but also participate in downstream signaling independent of G-protein activation [ 21 , 22 , 23 ]. Teixeira et al [ 16 ] report that Ang-(1-7) allows phosphorylation of ERK1/2 through a β-arrestin-dependent mechanism.…”