Related Experiment Video

Updated: Apr 14, 2026

Measuring Nucleotide Binding to Intact, Functional Membrane Proteins in Real Time
08:33

Measuring Nucleotide Binding to Intact, Functional Membrane Proteins in Real Time

Published on: March 11, 2021

2.4K

Ruling out pyridine dinucleotides as true TRPM2 channel activators reveals novel direct agonist

Balázs Tóth1, Iordan Iordanov1, László Csanády2

  • 1Department of Medical Biochemistry and MTA-SE Ion Channel Research Group, Semmelweis University, Budapest H-1094, Hungary Department of Medical Biochemistry and MTA-SE Ion Channel Research Group, Semmelweis University, Budapest H-1094, Hungary.

The Journal of General Physiology
|April 29, 2015
PubMed

Insights

ADPRP, not NAD, NAAD, or NAADP, directly activates the TRPM2 channel. This finding clarifies which pyridine dinucleotides directly bind to TRPM2, impacting research on cellular processes like insulin secretion.

Area of Science:

  • Molecular Biology
  • Ion Channel Physiology
  • Biochemistry

Background:

  • Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable cation channel involved in neuronal cell death, leukocyte activation, and insulin secretion.
  • TRPM2 is activated by intracellular ADP ribose (ADPR), but the direct activators among related pyridine dinucleotides remain unclear.

Purpose of the Study:

  • To determine the precise subset of pyridine dinucleotides that directly activate the TRPM2 channel.
  • To investigate whether nicotinamide-adenine-dinucleotide (NAD), nicotinic acid-adenine-dinucleotide (NAAD), or NAAD-2'-phosphate (NAADP) directly bind to and activate TRPM2.

Main Methods:

  • Utilized a heterologously expressed, affinity-purified ADPR hydrolase to remove contaminants from pyridine dinucleotide preparations.
  • Employed inside-out patch-clamp electrophysiology to apply purified dinucleotides to the cytosolic face of TRPM2 channels.
  • Assessed channel gating and activation by ADPR in the presence of purified NAD, NAAD, and NAADP.

Main Results:

  • Purified NAD, NAAD, and NAADP did not stimulate TRPM2 channel gating on their own.
  • These purified dinucleotides did not affect TRPM2 channel activation by ADPR.
  • ADPR-2'-phosphate (ADPRP) was identified as a direct agonist of the TRPM2 channel.

Conclusions:

  • Pyridine dinucleotides NAD, NAAD, and NAADP do not directly bind to or activate the TRPM2 channel.
  • ADPRP is a novel, direct agonist for the TRPM2 channel, suggesting its potential biological significance.
  • This study clarifies the direct molecular interactions with TRPM2, advancing understanding of its physiological roles.

More Related Videos

Author Spotlight: Developing Parmodulins to Target Protease-Activated Receptors for Inflammation Control07:13

Author Spotlight: Developing Parmodulins to Target Protease-Activated Receptors for Inflammation Control

Published on: May 24, 2024

1.1K
A Simple and Inexpensive Method for Determining Cold Sensitivity and Adaptation in Mice08:35

A Simple and Inexpensive Method for Determining Cold Sensitivity and Adaptation in Mice

Published on: March 17, 2015

15.9K

Related Concept Videos

IP3/DAG Signaling Pathway01:11

IP3/DAG Signaling Pathway

Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
16.1K
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...
8.4K
Biosynthesis of Nucleic Acids01:28

Biosynthesis of Nucleic Acids

Nucleic acid biosynthesis is a fundamental biochemical process that produces the purine and pyrimidine nucleotides essential for DNA and RNA synthesis. This pathway maintains a balanced nucleotide pool, preventing imbalances that could jeopardize genetic integrity and cellular function. Given the crucial role of nucleotides, their synthesis is tightly regulated to ensure proper cellular homeostasis.Purine BiosynthesisThe biosynthesis of purine nucleotides begins with ribose-5-phosphate, a...
1.6K
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
21.2K
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...
9.6K
Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship01:22

Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship

Cholinergic agonists or cholinomimetics mimic the action of acetylcholine to stimulate the parasympathetic nervous system. They are categorized into direct-acting and indirect-acting agents. The direct-acting cholinergic drugs induce the parasympathetic response by directly binding to the muscarinic or nicotine receptors. In comparison, the indirect-acting cholinergic drugs prevent acetylcholine hydrolysis, indirectly contributing to the extended parasympathetic response.
The direct-acting...
2.5K