A Cold-Sensing Receptor Encoded by a Glutamate Receptor Gene

Area of Science:

• Neuroscience
• Molecular Biology
• Sensory Biology

Background:

• Glutamate receptors are primarily known for their role in chemical synaptic transmission within the central nervous system.
• The molecular mechanisms underlying thermosensation, particularly cold detection, remain incompletely understood.

Purpose of the Study:

• To identify the molecular identity of cold-sensing receptors in the nematode C. elegans.
• To investigate the function of the kainate-type glutamate receptor GLR-3 in cold sensation and avoidance behavior.
• To determine if the mammalian homolog of GLR-3, GluK2, also functions as a cold receptor.

Main Methods:

• An unbiased genetic screen was performed in C. elegans to isolate cold-sensing mutants.
• The function of GLR-3 in cold sensation was analyzed in the ASER sensory neuron.
• G protein signaling pathways were investigated in relation to GLR-3's cold-sensing function.
• Heterologous expression systems were used to test the cold-sensing ability of vertebrate GLR-3 homologs (zebrafish, mouse, human GluK2).
• GluK2 function was assessed in mouse dorsal root ganglion (DRG) sensory neurons, including knockdown experiments.

Main Results:

• A mutant allele of the glr-3 gene was identified in a screen for cold-sensing mutants in C. elegans.
• GLR-3 was found to function as a cold sensor in the peripheral sensory neuron ASER, mediating cold-avoidance behavior.
• GLR-3 transmits cold signals through G protein signaling, independent of its canonical glutamate-gated channel activity, indicating a metabotropic function.
• Vertebrate homologs of GLR-3, specifically zebrafish, mouse, and human GluK2, demonstrated cold-sensing capabilities in heterologous systems.
• Knockdown of GluK2 in mouse DRG sensory neurons reduced sensitivity to cold (but not cool) temperatures.

Conclusions:

• The kainate-type glutamate receptor GLR-3 functions as a peripheral cold receptor in C. elegans.
• GLR-3 acts as a metabotropic cold receptor, utilizing G protein signaling independently of its ion channel activity.
• The identified cold-sensing mechanism involving GLR-3 is evolutionarily conserved, with vertebrate GluK2 homologs also functioning as cold receptors.
• This study reveals a novel role for a classical chemical receptor in thermal sensation, expanding our understanding of sensory biology.