Related Experiment Video
Updated: Apr 23, 2026
07:41
A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
8.4K
Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics
A E Cook1, S N Mistry, K J Gregory
1Drug Discovery Biology and Department of Pharmacology, Monash University, Parkville, Vic., Australia.
British Journal of Pharmacology
|September 16, 2014
Summary
Novel calcimimetics show biased signaling at calcium-sensing receptors, potentially improving hyperparathyroidism treatment by suppressing parathyroid hormone without affecting calcitonin.
Area of Science:
- Pharmacology
- Endocrinology
- Molecular Biology
Background:
- Cinacalcet for hyperparathyroidism can cause hypocalcemia due to calcium-sensing receptor (CaS receptor) activation and calcitonin release.
- Ligand-biased allosteric modulators of CaS receptors may offer improved therapies by selectively targeting desired signaling pathways.
Purpose of the Study:
- To characterize the ligand-biased signaling profiles of novel calcimimetics.
- To evaluate their effects on CaS receptor pathways involved in hormone regulation.
Main Methods:
- HEK293 cells expressing human CaS receptors were used to assess ligand bias.
- Measurements included intracellular calcium mobilization, inositol phosphate (IP1) accumulation, and ERK1/2 phosphorylation (pERK1/2).
Main Results:
- Phenylalkylamine calcimimetics and R,R-calcimimetic B/AC-265347 showed biased signaling towards IP1 accumulation and/or pERK1/2.
- AC-265347 did not promote CaS receptor trafficking, unlike other tested compounds.
- Nor-calcimimetic B exhibited unbiased signaling.
Conclusions:
- R,R-calcimimetic B and AC-265347's biased signaling may explain in vivo parathyroid hormone suppression without altering calcitonin levels.
- AC-265347 demonstrates a novel profile of CaS receptor modulation.
- Developing biased CaS receptor modulators offers a strategy for selective physiological responses in vivo.
Related Concept Videos
01:16Calmodulin-dependent Signaling
4.9K
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,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
4.9K
01:19Allosteric Proteins-ATCase
4.8K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
4.8K
01:08Allosteric Regulation
53.2K
Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
53.2K
01:58Cooperative Allosteric Transitions
7.3K
Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
7.3K
00:49Ligand Binding and Linkage
4.4K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
4.4K
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
4.5K
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
4.5K