Tmem45b modulates itch via endoplasmic reticulum calcium regulation

Area of Science:

• Neuroscience
• Molecular Biology
• Dermatology

Background:

• Itch sensation is a complex neurological process involving specific neuronal pathways.
• Dorsal Root Ganglion (DRG) neurons play a crucial role in transmitting itch signals.
• The precise molecular mechanisms regulating itch, particularly nonhistaminergic itch, require further elucidation.

Purpose of the Study:

• To investigate the role of Tmem45b in itch-associated DRG neurons.
• To determine the impact of Tmem45b deficiency on itch behavior and neuronal signaling.
• To elucidate the molecular mechanisms by which Tmem45b regulates itch.

Main Methods:

• Examined Tmem45b expression in DRG neuron subtypes.
• Assessed behavioral responses to pruritogens in Tmem45b conditional knockout (cKO) mice.
• Performed calcium imaging and bulk RNA-sequencing on DRG neurons from cKO mice.
• Analyzed Serca1 expression and endoplasmic reticulum (ER) calcium storage capacity.

Main Results:

• Tmem45b is expressed in itch-associated DRG neurons.
• Tmem45b cKO mice showed altered scratching behavior and alleviated chronic itch.
• Tmem45b deficiency impaired calcium responses in DRG neurons and downregulated Serca1, reducing ER calcium storage.
• Pharmacological inhibition of Serca1 mimicked the effects of Tmem45b deficiency on calcium signaling.

Conclusions:

• Tmem45b is critical for nonhistaminergic itch regulation.
• Tmem45b modulates ER calcium homeostasis via Serca1.
• Tmem45b deficiency reduces itch behavior and alters DRG neuron calcium signaling.
• Tmem45b represents a potential therapeutic target for managing chronic itch.