GPCRs for which the beta-arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent regulation) include ADRB2, F2RL1 and PTH1R. Recruits c-Src/SRC to ADRB2 resulting in ERK activation. ERK1/2 activated by the beta-arrestin scaffold is largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Acts as signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). Beta-arrestins function as multivalent adapter proteins that can switch the GPCR from a G-protein signaling mode that transmits short-lived signals from the plasma membrane via small molecule second messengers and ion channels to a beta-arrestin signaling mode that transmits a distinct set of signals that are initiated as the receptor internalizes and transits the intracellular compartment. Involved in the degradation of cAMP by recruiting cAMP phosphodiesterases to ligand-activated receptors. Involved in phopshorylation-dependent internalization of OPRD1 ands subsequent recycling. Involved in internalization of P2RY4 and UTP-stimulated internalization of P2RY2. Receptor resensitization then requires that receptor-bound arrestin is removed so that the receptor can be dephosphorylated and returned to the plasma membrane. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptors, for extended periods of time. Class A receptors, like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta-arrestin at or near the plasma membrane and undergo rapid recycling. Two different modes of arrestin-mediated internalization occur. Internalized arrestin-receptor complexes traffic to intracellular endosomes, where they remain uncoupled from G-proteins. However, the extent of beta-arrestin involvement appears to vary significantly depending on the receptor, agonist and cell type. The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). During homologous desensitization, beta-arrestins bind to the GPRK-phosphorylated receptor and sterically preclude its coupling to the cognate G-protein the binding appears to require additional receptor determinants exposed only in the active receptor conformation. The review aims to highlight the advantages of antibody mimics, and how they could be employed to overcome the issues and limitations of traditional ADCs.Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes. In this short review I will summarise the generation, modification, and application of emerging antibody fragments and synthetic antibody mimics, with a focus on their use as drug carriers. In response, the protein engineering community has begun to explore alternative high-binding protein scaffolds as antibody mimics. Studies have emerged suggesting that traditional IgG scaffolds may not be the optimal format for targeted payload delivery. However, despite the advantages, the field of ADCs has failed to live up to its full potential. The success of ADCs is evidenced by rapid adoption within the pharmaceuticals community many major companies have dedicated ADC research programmes. These important ligands have facilitated the development of effective therapies, particularly when conjugated to potent cytotoxic payloads i.e. The field of targeted therapeutics has benefitted immeasurably from the development of high-affinity antibodies.
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