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Related Concept Videos

Thermosensation01:43

Thermosensation

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...
GPCR Desensitization01:12

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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 produces two-second...
Phosphoinositides and PIPs01:42

Phosphoinositides and PIPs

Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Mechanically-gated Ion Channels01:12

Mechanically-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...
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,...

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Related Experiment Video

Updated: May 28, 2026

A Simple and Inexpensive Method for Determining Cold Sensitivity and Adaptation in Mice
08:35

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

Published on: March 17, 2015

Decrease in phosphatidylinositol 4,5-bisphosphate levels mediates desensitization of the cold sensor TRPM8 channels.

Yevgen Yudin1, Viktor Lukacs, Chike Cao

  • 1Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103, USA.

The Journal of Physiology
|October 19, 2011
PubMed
Summary

Cold and menthol activate TRPM8 channels, but their activity decreases due to phosphatidylinositol 4,5-bisphosphate depletion. This depletion, triggered by calcium influx and phospholipase C, is key to TRPM8 channel desensitization.

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Yeast Luminometric and Xenopus Oocyte Electrophysiological Examinations of the Molecular Mechanosensitivity of TRPV4
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Yeast Luminometric and Xenopus Oocyte Electrophysiological Examinations of the Molecular Mechanosensitivity of TRPV4

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Last Updated: May 28, 2026

A Simple and Inexpensive Method for Determining Cold Sensitivity and Adaptation in Mice
08:35

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

Published on: March 17, 2015

Yeast Luminometric and Xenopus Oocyte Electrophysiological Examinations of the Molecular Mechanosensitivity of TRPV4
12:09

Yeast Luminometric and Xenopus Oocyte Electrophysiological Examinations of the Molecular Mechanosensitivity of TRPV4

Published on: December 31, 2013

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Cell Physiology

Background:

  • Transient receptor potential melastatin 8 (TRPM8) channels, activated by cold and menthol, exhibit activity loss over time in the presence of extracellular calcium (Ca2+), a process known as desensitization.
  • The precise molecular mechanisms underlying TRPM8 desensitization remain incompletely understood, particularly the role of intracellular signaling pathways.

Purpose of the Study:

  • To investigate the role of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) in the desensitization of TRPM8 channels.
  • To elucidate the signaling cascade linking TRPM8 activation to PtdIns(4,5)P2 depletion and subsequent channel inactivation.

Main Methods:

  • Simultaneous patch-clamp electrophysiology and fluorescence-based measurements of cellular PtdIns(4,5)P2 levels.
  • Intracellular dialysis of PtdIns(4,5)P2 and its precursor, PtdIns(4)P.
  • Manipulation of intracellular Ca2+ levels using BAPTA-AM.
  • Utilizing a voltage-sensitive phosphatase (ci-VSP) for PLC-independent PtdIns(4,5)P2 depletion.
  • Assessing the role of MgATP and phosphatidylinositol 4-kinase (PI4K) in channel reactivation.

Main Results:

  • TRPM8 channel activation by cold or menthol leads to a decrease in cellular PtdIns(4,5)P2 levels, correlating temporally with current desensitization.
  • This PtdIns(4,5)P2 depletion is mediated by Ca2+-activated phospholipase C (PLC) and results in increased inositol 1,4,5 trisphosphate (InsP3) production.
  • Intracellular PtdIns(4,5)P2 replenishment inhibited desensitization, while its PLC-independent depletion inactivated TRPM8 currents.
  • MgATP and PI4K were involved in TRPM8 channel reactivation, and PKC inhibitors did not affect desensitization kinetics.

Conclusions:

  • Ca2+ influx through TRPM8 channels activates a Ca2+-sensitive PLC isoform, leading to PtdIns(4,5)P2 hydrolysis.
  • The resulting depletion of PtdIns(4,5)P2 is a critical mechanism driving the desensitization of both cold and menthol responses in TRPM8 channels.