Related Experiment Video

Updated: Aug 14, 2026

Drug-induced Sensitization of Adenylyl Cyclase: Assay Streamlining and Miniaturization for Small Molecule and siRNA Screening Applications
09:39

Drug-induced Sensitization of Adenylyl Cyclase: Assay Streamlining and Miniaturization for Small Molecule and siRNA Screening Applications

Published on: January 27, 2014

Conformational induction is the key process for activation of the AT1 receptor

James Ellis1, Philip Warburton, Dan Donnelly

  • 1Institute for Cardiovascular Research, University of Leeds, Leeds LS2 9JT, United Kingdom.

Biochemical Pharmacology
|December 14, 2005
PubMed

Insights

Angiotensin II type 1 (AT1) receptor activation primarily occurs through conformational induction, not selection. Modified receptors (CAMs) are necessary to observe conformational selection, indicating induction is the dominant mechanism.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Biochemistry

Background:

  • The mechanism of G protein-coupled receptor activation, specifically the AT1 receptor, remains debated.
  • Understanding AT1 receptor activation is crucial for developing targeted therapeutics.

Purpose of the Study:

  • To investigate whether AT1 receptor activation involves conformational selection or induction.
  • To characterize the pharmacological differences between wild-type and N111G CAM human AT1 receptors.

Main Methods:

  • Stable expression of wild-type and N111G CAM human AT1 receptors in HEK293 cells.
  • Evaluation of agonist potency and binding affinity using various angiotensin analogs.
  • Comparison of pharmacological profiles between wild-type and CAM receptors.

Main Results:

  • Angiotensin IV (Ang IV) showed significantly lower potency at wild-type AT1 receptors compared to CAM receptors.
  • [Sar1, Ile8]-Ang II acted as a full agonist only at the N111G CAM AT1 receptor.
  • Ang IV exhibited low-affinity binding to wild-type receptors but high-affinity binding to CAM receptors.

Conclusions:

  • Conformational induction is the predominant mechanism for AT1 receptor activation by agonists.
  • Conformational selection can only be observed in modified AT1 receptors (CAMs).
  • These findings provide critical insights into AT1 receptor activation dynamics and allosteric modulation.

More Related Videos

Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET10:59

Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET

Published on: August 17, 2022

Receptor Autoradiography Protocol for the Localized Visualization of Angiotensin II Receptors12:03

Receptor Autoradiography Protocol for the Localized Visualization of Angiotensin II Receptors

Published on: June 7, 2016

Related Concept Videos

GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

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 cells.
Two...
Activation of Integrins01:15

Activation of Integrins

Integrins bind ligands and transmit information from outside the cell to inside or vice-versa through an "outside-in signaling" or "inside-out signaling."
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding events provide an effective stimulus.
Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

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 affinity and are together...
The Two-State Receptor Model01:29

The Two-State Receptor Model

The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with one...
Calmodulin-dependent Signaling01:16

Calmodulin-dependent Signaling

Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
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...