Cav3.2 T-type calcium channel mediates acute itch and contributes to chronic itch and inflammation in experimental atopic dermatitis
Ji-Woong Ahn 1, Song-Ee Kim 2, Do-Young Kim 3, Inhye Jeong 2, Sohyun Kim 1, Seungsoo Chung 4, Sang Eun Lee 5
- PMID: 37863387
- DOI: 10.1016/j.jid.2023.07.029
Abstract
Voltage-gated calcium channels regulate neuronal excitability. The Cav3.2 isoform of the T-type voltage-activated calcium channel is expressed in sensory neurons and is implicated in pain transmission. However, its role in itch remains unclear. Herein, we demonstrated that Cav3.2 is expressed by mechanosensory and peptidergic subsets of mouse dorsal root ganglion (DRG) neurons and colocalized with TRPV1 and receptors for type 2 cytokines. Cav3.2-positive neurons innervate human skin. A deficiency of Cav3.2 reduces histamine, IL-4/IL-13, and thymic stromal lymphopoietin-induced itch in mice. Cav3.2 channels were upregulated in the DRGs of an atopic dermatitis (AD)-like mouse model and mediated neuronal excitability. Genetic knockout of Cav3.2 or T-type calcium channel blocker mibefradil treatment reduced spontaneous and mechanically induced scratching behaviors and skin inflammation in an AD-like mouse model. Substance P and vasoactive intestinal polypeptide levels were increased in the trigeminal ganglia (TG) from AD-like mouse model, and genetic ablation or pharmacological inhibition of Cav3.2 reduced their gene expression. Cav3.2 knockout also attenuated the pathologic changes in ex vivo skin explants co-cultured with TG neurons from AD-induced mice. Our study identifies the role of Cav3.2 in both histaminergic and non-histaminergic acute itch. Cav3.2 channel also contributes to AD-related chronic itch and neuroinflammation.
Keywords: Cav3.2; T-type voltage-activated calcium channel; atopic dermatitis; itch; neuroinflammation; substance P; vasoactive intestinal polypeptide.
