Anoctamin 1/TMEM16A in pruritoceptors is essential for Mas-related G protein receptor-dependent itch

Kim, Hyesu^1,3,7; Kim, Hyungsup^1,7; Cho, Hawon²; Lee, Byeongjun¹; Lu, Huan-Jun¹; Kim, Kyungmin¹; Chung, Sooyoung¹; Shim, Won-Sik⁴; Shin, Young Kee³; Dong, Xinzhong⁵; Wood, John N⁶; Oh, Uhtaek^1,3,*Author InformationPAIN: February 08, 2022 – Volume – Issue –doi: 10.1097/j.pain.0000000000002611

Abstract

Itch is an unpleasant sensation that evokes a desire to scratch. Pathologic conditions such as allergy or atopic dermatitis produce severe itching sensation. Mas-related G protein receptors (Mrgprs) are receptors for many endogenous pruritogens. However, signaling pathways downstream to these receptors in dorsal root ganglion (DRG) neurons are not yet understood. We found that Anoctamin 1 (ANO1), a Ca²⁺-activated chloride channel, is a transduction channel mediating Mrgprs-dependent itch signals. Genetic ablation of Ano1 in DRG neurons displayed a significant reduction in scratching behaviors in response to acute and chronic Mrgprs-dependent itch models and the epidermal hyperplasia induced by dry skin. In-vivo Ca²⁺ imaging and electrophysiological recording revealed that chloroquine and other agonists of Mrgpr receptors excited DRG neurons via ANO1. More importantly, the overexpression of Ano1 in DRG neurons of Ano1-deficient mice rescued the impaired itching observed in Ano1-deficient mice. These results demonstrate that ANO1 mediates the Mrgprs-dependent itch signaling in pruriceptors and provides clues to treating pathologic itch syndromes.

Cell. 2021 Jul 8;184(14):3762-3773.e10. doi: 10.1016/j.cell.2021.05.017. Epub 2021 Jun 15.

Sneezing reflex is mediated by a peptidergic pathway from nose to brainstem

Fengxian Li ¹, Haowu Jiang ¹, Xiaolei Shen ¹, Weishan Yang ¹, Changxiong Guo ¹, Zhiyao Wang ¹, Maolei Xiao ¹, Lian Cui ², Wenqin Luo ², Brian S Kim ³, Zhoufeng Chen ⁴, Andrew J W Huang ⁵, Qin Liu ⁶

• PMID: 34133943
• DOI: 10.1016/j.cell.2021.05.017

Abstract

Sneezing is a vital respiratory reflex frequently associated with allergic rhinitis and viral respiratory infections. However, its neural circuit remains largely unknown. A sneeze-evoking region was discovered in both cat and human brainstems, corresponding anatomically to the central recipient zone of nasal sensory neurons. Therefore, we hypothesized that a neuronal population postsynaptic to nasal sensory neurons mediates sneezing in this region. By screening major presynaptic neurotransmitters/neuropeptides released by nasal sensory neurons, we found that neuromedin B (NMB) peptide is essential for signaling sneezing. Ablation of NMB-sensitive postsynaptic neurons in the sneeze-evoking region or deficiency in NMB receptor abolished the sneezing reflex. Remarkably, NMB-sensitive neurons further project to the caudal ventral respiratory group (cVRG). Chemical activation of NMB-sensitive neurons elicits action potentials in cVRG neurons and leads to sneezing behavior. Our study delineates a peptidergic pathway mediating sneezing, providing molecular insights into the sneezing reflex arc.

Keywords: caudal ventral respiratory group; nasal sensory neurons; neuropeptide; sneeze; sneeze-evoking region.

mMrgprA3/mMrgprC11/hMrgprX1: potential therapeutic targets for allergic contact dermatitis induced pruritus in mice and human

Fengxian Li , Changming Wang , Danyou Hu , Xinyu Zhang , Ran Shen , Yuan Zhou , Yan Yang , Chan Zhu , Zongxiang Tang , Guang Yu 

•Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China •School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China •Key Laboratory for Chinese Medicine of Prevention and Treatment in Neurological Diseases, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China

Abstract

Background: Although the Mas-related G-protein-coupled receptors (Mrgprs) play essential roles in itch detection, their contribution to allergic contact dermatitis (ACD) associated itch remains unclear.

Objectives: To investigate whether Mrgprs are involved in ACD and whether Mrgprs can be identified as potential therapeutic targets.

Methods: Mrgpr-clusterΔ^-/- mice and human MrgprX1 (hMrgprX1) transgenic mice were applied to evalute the function of Mrgprs in oxazolone-induced ACD.

Results: Utilizing ACD model, we find that Mrgpr-clusterΔ^-/- mice display significantly reduced pruritus. Among 12 Mrgprs deleted in Mrgpr-clusterΔ^-/- mice, the expression of MrgprC11 and MrgprA3 are significantly increased in ACD model, which also innervate the skin and spinal cord at higher-than-normal densities, the proportions of dorsal root ganglia neurons responding to bovine adrenal medulla peptide 8-22 and chloroquine are also remarkably increased in ACD model and result in enhancing itch behavior. To study the function of human Mrgprs in ACD-induced itch, we utilize hMrgprX1 transgenic mice, which rescues the severe itch defect of Mrgpr-clusterΔ^-/- mice in ACD model. Remarkably, pharmacological blockade of hMrgprX1 significantly attenuates ACD itch in hMrgprX1 transgenic mouse.

Conclusions: Our study provides the first evidence that Mrgprs are involved in ACD induced chronic itch, which provides new avenues for itch management in ACD. This article is protected by copyright. All rights reserved.

Keywords: Allergic contact dermatitis; Mrgprs; pruritus; sensory neurons.