PPARγ ligands activate the ion channel TRPA1

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Peroxisome proliferator-activated receptors (PPARγ) are nuclear receptors involved in metabolic regulation.
• Synthetic PPARγ agonists, like thiazolidinediones, are used as antidiabetic drugs and have shown analgesic potential.
• The transient receptor potential A1 (TRPA1) channel is a key sensor of noxious stimuli in sensory neurons.

Purpose of the Study:

• To investigate the effects of various PPARγ ligands on TRPA1 channel activity in sensory neurons and cell lines.
• To determine if PPARγ ligands can induce pain responses mediated by TRPA1.
• To elucidate the mechanism of interaction between PPARγ ligands and TRPA1.

Main Methods:

• Intracellular calcium (Ca2+) measurements in TRPA1-expressing cells and mouse dorsal root ganglion (DRG) neurons.
• Voltage-clamp recordings to assess TRPA1 channel function.
• Intraplantar administration of troglitazone in wild-type and Trpa1 knockout mice.
• Molecular docking studies to predict ligand-receptor interactions.

Main Results:

• Several PPARγ ligands (troglitazone, rosiglitazone, nTZDpa) and a PPARγ antagonist (GW9662) induced Ca2+ influx in TRPA1-expressing cells and DRG neurons.
• These responses were dependent on TRPA1 expression and were blocked by a TRPA1 antagonist.
• Ligand activation of TRPA1 occurred via non-covalent interactions, independent of cysteine modification.
• Intraplantar troglitazone induced pain responses in wild-type mice but not in Trpa1 knockout mice.
• Molecular docking suggested overlapping binding sites for nTZDpa and troglitazone within TRPA1.

Conclusions:

• Multiple PPARγ ligands act as TRPA1 agonists, modulating sensory neuron activity.
• PPARγ ligands can induce TRPA1-dependent nociception.
• nTZDpa is a potential pharmacological tool for studying TRPA1 function.