Table_2_β-Arrestin Based Receptor Signaling Paradigms: Potential Therapeutic Targets for Complex Age-Related Disorders.XLSX

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.

G蛋白偶联受体（G protein coupled receptors, GPCRs）最初被鉴定为通过调控鸟苷酸（G）结合蛋白以触发下游效应的信号转导分子。针对这一信号范式的药物开发应用，已形成一个覆盖当前近50%药典药物的药物研发领域。自20世纪90年代末的突破性发现至今，现已明确GPCRs还可通过调控β-阻遏蛋白（β-arrestin）功能，产生有效信号级联反应。β-阻遏蛋白最初被认为仅能调控受体脱敏与受体内化——这以视紫红质脱敏过程中视觉阻遏蛋白的作用为典型例证。近20年前的研究发现，依赖β-阻遏蛋白的有效GPCR信号通路，与依赖可溶性第二信使系统且具有瞬时性的G蛋白信号通路截然不同：前者高度依赖多蛋白复合物的形成并能产生持久的细胞效应，而非仅终止GPCR的信号转导。此后，β-阻遏蛋白信号通路首次被证实可通过不依赖G蛋白的方式激活丝裂原活化蛋白激酶（mitogen activated protein kinase）信号通路，并最终启动蛋白质转录，从而调控下游蛋白的表达模式。尽管目前学界正探索开发β-阻遏蛋白偏向性或功能选择性配体，但尚未有研究探讨其在治疗年龄相关性疾病中可能存在的情境特异性。依赖β-阻遏蛋白的信号通路能够调控复杂且多维度的蛋白表达模式，这使得该治疗策略具备可行性——因为治疗复杂的年龄相关性疾病，往往需要能够发挥网络层面药效谱的治疗药物。我们认为，靶向β-阻遏蛋白等不依赖G蛋白的效应分子的治疗手段，将有助于开发针对疾病或年龄特异性情境的精准医学疗法，其药效谱可按需定制。