The Role of Individual Residues in the N-Terminus of Arrestin-1 in Rhodopsin Binding.

Sequences and three-dimensional structures of the four vertebrate arrestins are very similar, yet in sharp contrast to other subtypes, arrestin-1 demonstrates exquisite selectivity for the active phosphorylated form of its cognate receptor, rhodopsin. The N-terminus participates in receptor binding and serves as the anchor of the C-terminus, the release of which facilitates arrestin transition into a receptor-binding state. We tested the effects of substitutions of fourteen residues in the N-terminus of arrestin-1 on the binding to phosphorylated and unphosphorylated light-activated rhodopsin of wild-type protein and its enhanced mutant with C-terminal deletion that demonstrates higher binding to both functional forms of rhodopsin.

A small molecule enhances arrestin-3 binding to the β-adrenergic receptor.

G protein-coupled receptor (GPCR) signaling is terminated by arrestin binding to a phosphorylated receptor. Binding propensity has been shown to be modulated by stabilizing the pre-activated state of arrestin through point mutations or C-tail truncation. Here, we hypothesize that pre-activated rotated states can be stabilized by small molecules, and this can promote binding to phosphorylation-deficient receptors, which underly a variety of human disorders.

Flavors of GPCR signaling bias.

GPCRs are inherently flexible molecules existing in an equilibrium of multiple conformations. Binding of GPCR agonists shifts this equilibrium. Certain agonists can increase the fraction of active-like conformations that predispose the receptor to coupling to a particular signal transducer or a select group of transducers.

Arrestin-3-assisted activation of JNK3 mediates dopaminergic behavioral sensitization.

In rodents with unilateral ablation of neurons supplying dopamine to the striatum, chronic treatment with the dopamine precursor L-DOPA induces a progressive increase of behavioral responses, a process known as behavioral sensitization. This sensitization is blunted in arrestin-3 knockout mice. Using virus-mediated gene delivery to the dopamine-depleted striatum of these mice, we find that the restoration of arrestin-3 fully rescues behavioral sensitization, whereas its mutant defective in c-Jun N-terminal kinase (JNK) activation does not.

GPCR-dependent and -independent arrestin signaling.

Biological activity of free arrestins is often overlooked. Based on available data, we compare arrestin-mediated signaling that requires and does not require binding to G-protein-coupled receptors (GPCRs). Receptor-bound arrestins activate ERK1/2, Src, and focal adhesion kinase (FAK).

Arrestins: A Small Family of Multi-Functional Proteins.

The first member of the arrestin family, visual arrestin-1, was discovered in the late 1970s. Later, the other three mammalian subtypes were identified and cloned. The first described function was regulation of G protein-coupled receptor (GPCR) signaling: arrestins bind active phosphorylated GPCRs, blocking their coupling to G proteins.

KSHV genome harbors both constitutive and lytically induced enhancers.

Kaposi's sarcoma-associated herpesvirus (KSHV) belongs to the gamma-herpesvirus family and is a well-known human oncogenic virus. In infected cells, the viral genome of 165 kbp is circular DNA wrapped in chromatin. The tight control of gene expression is critical for latency, the transition into the lytic phase, and the development of viral-associated malignancies.

Why selective screening for asymptomatic carotid stenosis is currently appropriate: a special report.

Introduction: Two of the main reasons recent guidelines do not recommend routine population-wide screening programs for asymptomatic carotid artery stenosis (AsxCS) is that screening could lead to an increase of carotid revascularization procedures and that such mass screening programs may not be cost-effective. Nevertheless, selective screening for AsxCS could have several benefits. This article presents the rationale for such a program.

Arrestin-3 binds parkin and enhances parkin-dependent mitophagy.

Arrestins were discovered for their role in homologous desensitization of G-protein-coupled receptors (GPCRs). Later non-visual arrestins were shown to regulate several signaling pathways. Some of these pathways require arrestin binding to GPCRs, the regulation of others is receptor independent.

Arrestin-3-assisted activation of JNK3 mediates dopaminergic behavioral and signaling plasticity in vivo.

In rodents with unilateral ablation of the substantia nigra neurons supplying dopamine to the striatum, chronic treatment with the dopamine precursor L-DOPA or dopamine agonists induces a progressive increase of behavioral responses, a process known as behavioral sensitization. The sensitization is blunted in arrestin-3 knockout mice. Using virus-mediated gene delivery to the dopamine-depleted striatum of arrestin-3 knockout mice, we found that the restoration of arrestin-3 fully rescued behavioral sensitization, whereas its mutant defective in JNK activation did not.

In-Cell Arrestin-Receptor Interaction Assays.

G protein-coupled receptors (GPCRs) represent ∼30% of current drug targets. Ligand binding to these receptors activates G proteins and arrestins, which function in different signaling pathways. Given that functionally selective or biased ligands preferentially activate one of these two groups of pathways, they may be superior medications for certain disease states.

Expression of Untagged Arrestins in E. coli and Their Purification.

Purified arrestin proteins are necessary for biochemical, biophysical, and structural studies of these versatile regulators of cell signaling. Described herein is a basic protocol for arrestin expression in Escherichia coli and purification of tag-free wild-type and mutant arrestins. The method includes ammonium sulfate precipitation of arrestins from cell lysates, followed by Heparin-Sepharose chromatography.

Arrestin-3-Dependent Activation of c-Jun N-Terminal Kinases (JNKs).

Only 1 out of 4 mammalian arrestin subtypes, arrestin-3, facilitates the activation of c-Jun N-terminal kinase (JNK) family kinases. Here, we describe two different sets of protocols used for elucidating the mechanisms involved. One is based on reconstitution of signaling modules from the following purified proteins: arrestin-3, MKK4, MKK7, JNK1, JNK2, and JNK3.

Do arrestin oligomers have specific functions?

Arrestins are a small family of versatile regulators of cell signaling. Arrestins regulate signaling and trafficking of G protein-coupled receptors, regulate and direct to particular subcellular compartments numerous protein kinases, ubiquitin ligases, etc. Three out of four arrestin subtypes expressed in vertebrates self-associate, each forming oligomers of a distinct size and shape.

Pseudoaneurysm temporary embolization as a new method for the management of catheter-related complication.

A new minimally invasive method for the management of catheter-related pseudoaneurysms (PSAs) using percutaneous temporary guidewire embolization (TGE) is presented. We performed percutaneous insertion of a flexible 0.018-in.

GPCR Binding and JNK3 Activation by Arrestin-3 Have Different Structural Requirements.

Arrestins bind active phosphorylated G protein-coupled receptors (GPCRs). Among the four mammalian subtypes, only arrestin-3 facilitates the activation of JNK3 in cells. In available structures, Lys-295 in the lariat loop of arrestin-3 and its homologue Lys-294 in arrestin-2 directly interact with the activator-attached phosphates.

Mechanisms of Arrestin-Mediated Signaling.

Arrestins were first discovered as proteins that selectively bind active phosphorylated GPCRs and suppress (arrest) their G protein-mediated signaling. Nonvisual arrestins are also recognized as signaling proteins regulating a variety of cellular pathways. Arrestins are highly flexible; they can assume many different conformations.

Functional Role of Arrestin-1 Residues Interacting with Unphosphorylated Rhodopsin Elements.

Arrestin-1, or visual arrestin, exhibits an exquisite selectivity for light-activated phosphorylated rhodopsin (P-Rh*) over its other functional forms. That selectivity is believed to be mediated by two well-established structural elements in the arrestin-1 molecule, the activation sensor detecting the active conformation of rhodopsin and the phosphorylation sensor responsive to the rhodopsin phosphorylation, which only active phosphorylated rhodopsin can engage simultaneously. However, in the crystal structure of the arrestin-1-rhodopsin complex there are arrestin-1 residues located close to rhodopsin, which do not belong to either sensor.

GPCR binding and JNK3 activation by arrestin-3 have different structural requirements.

Arrestins bind active phosphorylated G protein-coupled receptors (GPCRs). Among the four mammalian subtypes, only arrestin-3 facilitates the activation of JNK3 in cells. In available structures, Lys-295 in the lariat loop of arrestin-3 and its homologue Lys-294 in arrestin-2 directly interact with the activator-attached phosphates.

-Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives.

The two -arrestins, -arrestin-1 and -2 (systematic names: arrestin-2 and -3, respectively), are multifunctional intracellular proteins that regulate the activity of a very large number of cellular signaling pathways and physiologic functions. The two proteins were discovered for their ability to disrupt signaling via G protein-coupled receptors (GPCRs) via binding to the activated receptors. However, it is now well recognized that both -arrestins can also act as direct modulators of numerous cellular processes via either GPCR-dependent or -independent mechanisms.

A boost in learning by removing nuclear phosphodiesterases and enhancing nuclear cAMP signaling.

cAMP signaling in the nucleus leads to the expression of immediate early genes in neurons and learning and memory. In this issue of , Martinez . found that activation of the β-adrenergic receptor enhances nuclear cAMP signaling that supports learning and memory in mice by removing the phosphodiesterase PDE4D5 from the nucleus through arrestin3 bound to the internalized receptor.

[Cardiovascular effects of omega-3 polyunsaturated fatty acids: position of omega-3 polyunsaturated fatty acids in Russian and international guidelines. Council of Experts].

This Expert Council focuses on the meta-analysis of studies on the risk of atrial fibrillation (AF) in patients taking omega-3 polyunsaturated fatty acids (PUFA) and of data on the omega-3 PUFA treatment in patients with cardiovascular and kidney diseases.The major statements of the Expert Council: the meta-analysis of AF risk in patients taking omega-3 PUFA showed an increased risk of this arrhythmia. However, it should be taken into account that the risk of complications was low, and there was no significant increase in the risk of AF when omega-3 PUFA was used at a dose of ≤1 g and a standard dose of the only omega-3 PUFA drug registered in the Russian Federation, considering all AF episodes in the ASCEND study.