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Related Concept Videos

Cell-surface Signaling01:21

Cell-surface Signaling

Hormones—or any molecule that binds to a receptor, known as a ligand—that are lipid-insoluble (water-soluble) are not able to diffuse across the cell membrane. In order to be able to affect a cell without entering it, these hormones bind to receptors on the cell membrane. When a first messenger, a hormone, binds to a receptor, a signal cascade is set off, causing second messengers, proteins inside the cell, to become activated, resulting in downstream effects.
Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

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.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

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 the...
Signal Transduction: Overview01:26

Signal Transduction: Overview

Cells respond to many types of information, often through receptor proteins positioned on the membrane. They respond to chemical signals, such as hormones, neurotransmitters, and other signaling molecules, initiating a series of molecular reactions to produce an appropriate response. This is called signal transduction. Cells also coordinate different responses elicited by the same signaling molecule via mediators, allowing molecular cross-talk.
Typically, signal transduction involves three...
Amplifying Signals via Second Messengers01:15

Amplifying Signals via Second Messengers

Many receptor binding ligands are hydrophilic; they do not cross the cell membrane but bind to cell-surface receptors. Thus, their message must be relayed by second messengers present in the cell cytoplasm. There are several second messenger pathways, each with its own way of relaying information. For example, the G protein-coupled receptors can activate both phosphoinositol and cyclic AMP (cAMP) second messenger pathways. The phosphoinositol pathway is active when the receptor induces...

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Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET
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Membrane signalling complexes: implications for development of functionally selective ligands modulating heptahelical

Graciela Piñeyro1

  • 1Centre de Recherche Fernand Seguin, Hôpital L.H. Lafontaine, Université de Montréal, Canada. graciela.pineyro.filpo@umontreal.ca

Cellular Signalling
|September 16, 2008
PubMed
Summary

New drug development focuses on functional selectivity, where ligands stabilize specific receptor conformations to direct signaling pathways. This approach targets constitutive signaling arrays in heptahelical receptors for precise therapeutic effects.

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Drug Discovery

Background:

  • Technological advancements have revolutionized drug efficacy evaluation.
  • Heptahelical receptors (GPCRs) can adopt multiple active conformations with distinct signaling properties.
  • Ligands can stabilize specific receptor conformations, directing downstream signaling.

Purpose of the Study:

  • To explore the concept of functional selectivity (stimulus trafficking) in receptor signaling.
  • To review evidence for constitutive signaling arrays formed by heptahelical receptors.
  • To assess the potential of these arrays as targets for functional selectivity ligands.

Main Methods:

  • Review of existing scientific literature and evidence.
  • Analysis of molecular resolution assay data.
  • Conceptual framework development for receptor-ligand interactions.

Main Results:

  • Ligand-induced stabilization of specific receptor conformations allows for selective pathway activation.
  • Heptahelical receptors form pre-assembled, constitutive signaling complexes.
  • These complexes represent viable targets for developing drugs with functional selectivity.

Conclusions:

  • Functional selectivity offers a precise method for regulating receptor signaling.
  • Constitutive signaling arrays are integral units with therapeutic potential.
  • Targeting these arrays can lead to highly specific drug actions.