Las arrestinas (abreviadas Arr ) son una pequeña familia de proteínas importantes para regular la transducción de señales en los receptores acoplados a proteína G. [2] [3] Las arrestinas fueron descubiertas por primera vez como parte de un mecanismo conservado de dos pasos para regular la actividad de los receptores acoplados a proteína G (GPCR) en el sistema visual de rodopsina por Hermann Kühn, Scott Hall y Ursula Wilden [4 ] y en el sistema β-adrenérgico por Martin J. Lohse y colaboradores. [5] [6]
En respuesta a un estímulo, los GPCR activan proteínas G heterotriméricas . Para desactivar esta respuesta o adaptarse a un estímulo persistente, es necesario desensibilizar los receptores activos. El primer paso en la desensibilización es la fosforilación del receptor por una clase de serina/treonina quinasas llamadas quinasas receptoras acopladas a proteína G (GRK). La fosforilación de GRK prepara específicamente el receptor activado para la unión de arrestina. La unión de la arrestina al receptor bloquea aún más la señalización mediada por la proteína G y se dirige a los receptores para su internalización, y redirige la señalización a vías alternativas independientes de la proteína G, como la señalización de la β-arrestina. [7] [8] [9] [10] [6] Además de los GPCR, las arrestinas se unen a otras clases de receptores de la superficie celular y a una variedad de otras proteínas de señalización. [11]
Los mamíferos expresan cuatro subtipos de arrestina y cada subtipo de arrestina se conoce con múltiples alias. El nombre sistemático de arrestina (1-4) más los alias más utilizados para cada subtipo de arrestina se enumeran en negrita a continuación:
Fish and other vertebrates appear to have only three arrestins: no equivalent of arrestin-2, which is the most abundant non-visual subtype in mammals, was cloned so far. The proto-chordate Ciona intestinalis (sea squirt) has only one arrestin, which serves as visual in its mobile larva with highly developed eyes, and becomes generic non-visual in the blind sessile adult. Conserved positions of multiple introns in its gene and those of our arrestin subtypes suggest that they all evolved from this ancestral arrestin.[12] Lower invertebrates, such as roundworm Caenorhabditis elegans, also have only one arrestin. Insects have arr1 and arr2, originally termed “visual arrestins” because they are expressed in photoreceptors, and one non-visual subtype (kurtz in Drosophila). Later arr1 and arr2 were found to play an important role in olfactory neurons and renamed “sensory”. Fungi have distant arrestin relatives involved in pH sensing.
One or more arrestin is expressed in virtually every eukaryotic cell. In mammals, arrestin-1 and arrestin-4 are largely confined to photoreceptors, whereas arrestin-2 and arrestin-3 are ubiquitous. Neurons have the highest expression level of both non-visual subtypes. In neuronal precursors both are expressed at comparable levels, whereas in mature neurons arrestin-2 is present at 10-20 fold higher levels than arrestin-3.
Arrestins block GPCR coupling to G proteins in two ways. First, arrestin binding to the cytoplasmic face of the receptor occludes the binding site for heterotrimeric G-protein, preventing its activation (desensitization).[13] Second, arrestin links the receptor to elements of the internalization machinery, clathrin and clathrin adaptor AP2, which promotes receptor internalization via coated pits and subsequent transport to internal compartments, called endosomes. Subsequently, the receptor could be either directed to degradation compartments (lysosomes) or recycled back to the plasma membrane where it can again signal. The strength of arrestin-receptor interaction plays a role in this choice: tighter complexes tend to increase the probability of receptor degradation (Class B), whereas more transient complexes favor recycling (Class A), although this “rule” is far from absolute.[2] More recently direct interactions between Gi/o family G proteins and Arrestin were discovered downstream of multiple receptors, regardless of canonical G protein coupling.[14] These recent findings introduce a GPCR signaling mechanism distinct from canonical G protein activation and β-arrestin desensitization in which GPCRs cause the formation of Gαi:β-arrestin signaling complexes.
Arrestins are elongated molecules, in which several intra-molecular interactions hold the relative orientation of the two domains. Unstimulated cell arrestins are localized in the cytoplasm in a basal “inactive” conformation. Active phosphorylated GPCRs recruit arrestin to the plasma membrane. Receptor binding induces a global conformational change that involves the movement of the two arrestin domains and the release of its C-terminal tail that contains clathrin and AP2 binding sites. Increased accessibility of these sites in receptor-bound arrestin targets the arrestin-receptor complex to the coated pit. Arrestins also bind microtubules (part of the cellular “skeleton”), where they assume yet another conformation, different from both free and receptor-bound form. Microtubule-bound arrestins recruit certain proteins to the cytoskeleton, which affects their activity and/or redirects it to microtubule-associated proteins.
Arrestins shuttle between cell nucleus and cytoplasm. Their nuclear functions are not fully understood, but it was shown that all four mammalian arrestin subtypes remove some of their partners, such as protein kinase JNK3 or the ubiquitin ligase Mdm2, from the nucleus. Arrestins also modify gene expression by enhancing transcription of certain genes.