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Related Concept Videos

GPCR Desensitization01:12

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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
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Location-biased β-arrestin conformations direct GPCR signaling.

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Beta-arrestins (β-arrestins) direct location-biased signaling of G protein-coupled receptors (GPCRs). Distinct β-arrestin conformations in different cellular locations influence signaling pathways like ERK.

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Area of Science:

  • Cellular Biology
  • Molecular Pharmacology
  • Biochemistry

Background:

  • Beta-arrestins (β-arrestins) are key regulators of G protein-coupled receptor (GPCR) function, involved in desensitization, internalization, and signaling.
  • GPCRs can signal from various subcellular locations, a phenomenon termed 'location bias', leading to distinct signaling outcomes.

Purpose of the Study:

  • To investigate how β-arrestins mediate location-biased signaling of the angiotensin II type 1 receptor (AT1R).
  • To explore the distinct conformations and signaling roles of β-arrestin 1 and β-arrestin 2 in different subcellular compartments.

Main Methods:

  • Utilized bioluminescence resonance energy transfer (BRET) conformational biosensors to monitor β-arrestin conformations.
  • Employed extracellular signal-regulated kinase (ERK) activity reporters to assess signaling dynamics.
  • Investigated AT1R signaling in response to angiotensin II and a β-arrestin-biased agonist (TRV023).

Main Results:

  • β-arrestin 1 and β-arrestin 2 adopted distinct conformations in different subcellular locations upon AT1R activation.
  • These distinct conformations correlated with differential ERK activation profiles.
  • Identified receptor-free, activated β-arrestins at the plasma membrane, promoting G protein-independent ERK activation.

Conclusions:

  • β-arrestins play nuanced roles in directing GPCR location-biased signaling beyond canonical G protein pathways.
  • The conformation and subcellular location of β-arrestins are critical determinants of specific signaling outcomes.
  • Findings advance the understanding of GPCR signaling complexity and β-arrestin function.