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Plethora of functions packed into 45 kDa arrestins: biological implications and possible therapeutic strategies

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Abstract

Mammalian arrestins are a family of four highly homologous relatively small ~ 45 kDa proteins with surprisingly diverse functions. The most striking feature is that each of the two non-visual subtypes can bind hundreds of diverse G protein-coupled receptors (GPCRs) and dozens of non-receptor partners. Through these interactions, arrestins regulate the G protein-dependent signaling by the desensitization mechanisms as well as control numerous signaling pathways in the G protein-dependent or independent manner via scaffolding. Some partners prefer receptor-bound arrestins, some bind better to the free arrestins in the cytoplasm, whereas several show no apparent preference for either conformation. Thus, arrestins are a perfect example of a multi-functional signaling regulator. The result of this multi-functionality is that reduction (by knockdown) or elimination (by knockout) of any of these two non-visual arrestins can affect so many pathways that the results are hard to interpret. The other difficulty is that the non-visual subtypes can in many cases compensate for each other, which explains relatively mild phenotypes of single knockouts, whereas double knockout is lethal in vivo, although cultured cells lacking both arrestins are viable. Thus, deciphering the role of arrestins in cell biology requires the identification of specific signaling function(s) of arrestins involved in a particular phenotype. This endeavor should be greatly assisted by identification of structural elements of the arrestin molecule critical for individual functions and by the creation of mutants where only one function is affected. Reintroduction of these biased mutants, or introduction of monofunctional stand-alone arrestin elements, which have been identified in some cases, into double arrestin-2/3 knockout cultured cells, is the most straightforward way to study arrestin functions. This is a laborious and technically challenging task, but the upside is that specific function of arrestins, their timing, subcellular specificity, and relations to one another could be investigated with precision.

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Abbreviations

GPCR:

G protein-coupled receptor

NSF:

N-ethylmaleimide sensitive fusion protein

EPR:

Electron paramagnetic resonance

DEER:

Double electron–electron resonance

NMR:

Nuclear magnetic resonance

ERK:

Extracellular signal-regulated kinase

JNK:

c-Jun N-terminal kinase

ASK:

Apoptosis signal-regulating kinase

MAPK:

Mitogen-activated protein kinase

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Acknowledgements

This study was supported in part by NIH Grants RO1 EY011500, R35 GM122491, and Cornelius Vanderbilt Endowed Chair (VVG), and RO1s NS065868 and DA030103 (EVG).

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  1. Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA

    Vsevolod V. Gurevich & Eugenia V. Gurevich

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  1. Vsevolod V. Gurevich
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  2. Eugenia V. Gurevich
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Correspondence to Vsevolod V. Gurevich.

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Gurevich, V.V., Gurevich, E.V. Plethora of functions packed into 45 kDa arrestins: biological implications and possible therapeutic strategies. Cell. Mol. Life Sci. 76, 4413–4421 (2019). https://doi.org/10.1007/s00018-019-03272-5

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  • DOI: https://doi.org/10.1007/s00018-019-03272-5

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