Related Experiment Video

Updated: Dec 7, 2025

Oligopeptide Competition Assay for Phosphorylation Site Determination
09:16

Oligopeptide Competition Assay for Phosphorylation Site Determination

Published on: May 18, 2017

8.7K

Niclosamide activates the AMP-activated protein kinase complex containing the β2 subunit independently of AMP

Tsukasa Suzuki1, Momoko Kojima1, Yu Matsumoto1

  • 1Department of Agricultural Chemistry, Faculty of Applied Biosciences, Tokyo University of Agriculture, Setagaya-ku, Tokyo, 156-8502, Japan.

Biochemical and Biophysical Research Communications
|September 30, 2020
PubMed

Insights

Niclosamide activates AMP-activated protein kinase (AMPK) through a novel mechanism. This FDA-approved drug targets the AMPK complex

Area of Science:

  • Biochemistry
  • Cellular Metabolism
  • Pharmacology

Background:

  • AMP-activated protein kinase (AMPK) is crucial for cellular energy homeostasis, making it a therapeutic target for metabolic syndrome.
  • Niclosamide, an anthelmintic drug, has shown potential in improving glucose levels and reducing hepatic steatosis through AMPK activation.
  • The precise mechanism by which niclosamide activates AMPK, particularly its interaction with mitochondrial uncoupling, requires further elucidation.

Purpose of the Study:

  • To investigate the detailed mechanism of AMPK activation by niclosamide.
  • To determine if niclosamide's action is dependent on the AMP/ATP ratio.
  • To identify specific subunits and residues involved in niclosamide-mediated AMPK activation.

Main Methods:

  • Biochemical assays to measure AMPK activity in response to niclosamide.
  • Analysis of AMPK complex composition, focusing on different beta subunits (β1 and β2).
  • Site-directed mutagenesis of the β2 subunit (Ser108) to assess its role in niclosamide's effect.

Main Results:

  • Niclosamide activates the AMPK complex, including the AMP-insensitive γ subunit.
  • AMPK activation by niclosamide is enhanced with the β2 subunit compared to the β1 subunit.
  • Mutation of Ser108 in the β2 subunit abrogated niclosamide-induced AMPK activation.
  • Niclosamide activates AMPK independently of changes in the cellular AMP/ATP ratio.

Conclusions:

  • Niclosamide employs a novel mechanism to activate AMPK, distinct from increasing the AMP/ATP ratio.
  • The β2 subunit, specifically Ser108, plays a critical role in niclosamide's AMPK activation pathway.
  • These findings offer new insights into AMPK regulation and the therapeutic potential of niclosamide for metabolic disorders.
Keywords:
AMPKAMPKβ2 subunitDiabetesMetforminNiclosamide

More Related Videos

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators07:41

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators

Published on: February 20, 2018

9.3K
Drug-induced Sensitization of Adenylyl Cyclase: Assay Streamlining and Miniaturization for Small Molecule and siRNA Screening Applications09:39

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

Published on: January 27, 2014

13.0K

Related Concept Videos

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,...
5.8K
cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
7.6K
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...
7.8K
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...
16.0K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
4.9K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
7.5K