The calcium-permeable non-selective cation channel TRPM2 is modulated by cellular acidification
John G Starkus1, Andrea Fleig, Reinhold Penner
1University of Hawaii, Pacific Biosciences Research Center, Queens Medical Center, University Tower, 814, 1356 Lusitania Street, Honolulu, HI 96813, USA. johns@pbrc.hawaii.edu
The Journal of Physiology
|March 3, 2010
Summary
Protons inhibit the TRPM2 channel by entering the cell and binding to an intracellular site, affecting its function in inflammation and cell death. This proton block is voltage-dependent and influenced by calcium.
Area of Science:
- Ion channel physiology
- Molecular cell biology
- Inflammation research
Background:
- TRPM2 channels are calcium-permeable cation channels involved in inflammation and cell death.
- TRPM2 is activated by ADP-ribose and modulated by reactive oxygen species and calcium.
- The role of pH in TRPM2 channel regulation was not well understood.
Purpose of the Study:
- To investigate the effects of extracellular and intracellular acidification on TRPM2 channel activity.
- To elucidate the mechanism by which protons regulate TRPM2 function.
Main Methods:
- Heterologous expression of TRPM2 in HEK293 cells.
- Electrophysiological recordings (whole-cell and single-channel) to measure TRPM2 currents.
- Investigation of voltage dependence and effects of buffering capacity and calcium.
Main Results:
- Extracellular acidification inhibited TRPM2 with an IC50 of pH 6.5; intracellular pH of 6 completely suppressed the channel.
- Proton inhibition was voltage-dependent, most effective at negative potentials.
- Protons appear to permeate the TRPM2 channel to interact with an intracellular site, competing with Na+ and Ca2+.
Conclusions:
- Protons act as inhibitors of TRPM2 channels, with distinct effects depending on their location (extra- vs. intracellular).
- Proton-induced TRPM2 inhibition involves competitive antagonism at an intracellular calcium-binding site.
- These findings reveal a novel regulatory mechanism for TRPM2, impacting its role in cellular processes sensitive to pH changes.
Related Concept Videos
01:27Feedback Regulation of Calcium Concentration
Calcium is an essential signaling molecule required for various cellular functions. Calcium pumps and ion channels on cell and organellar membranes, such as those on the endoplasmic reticulum (ER), regulate calcium concentrations inside the cell. They remain closed, keeping the cytosolic calcium levels low at a resting state.
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
01:16Calmodulin-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,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
01:12Mechanically-gated Ion Channels
Mechanically-gated ion channels are proteins found in eukaryotic and prokaryotic cell membranes that open in response to mechanical stress. Tension, compression, swelling, and shear stress can alter the conformation of the protein, opening a transmembrane channel that allows the passage of ions for signal transmission. In eukaryotes, mechanically-gated channels are distributed in several regions like the neurons, lungs, skin, bladder, and heart, where they play critical roles in numerous...
01:28pH Regulation in Cells
pH plays a critical role in maintaining normal cellular activities. It helps maintain the structure and function of various proteins, dictates the charge on cellular membranes, and is crucial for metabolic reactions inside the cell. Moreover, cells use the energy from the proton motive force to generate ATP.
Cytosolic pH
Under physiological conditions, the cytosolic pH is slightly more acidic than the extracellular pH. However, cells must prevent further acidification of their cytosol to...
Cytosolic pH
Under physiological conditions, the cytosolic pH is slightly more acidic than the extracellular pH. However, cells must prevent further acidification of their cytosol to...
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
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...
01:43Thermosensation
Peripheral thermosensation is the perception of external temperature. A change in temperature (on the surface of the skin and other tissues) is detected by a family of temperature-sensitive ion channels called Transient Receptor Potential, or TRP, receptors. These receptors are located on free nerve endings. Those detecting cold temperatures are closer to the surface of the skin than the nerve endings detecting warmth. These thermoTRP channels, while temperature selective, have relatively...