Divergent sensory pathways of sneezing and coughing

Haowu Jiang ¹⁴, Huan Cui ¹⁴, Mengyu Chen ¹, Fengxian Li ¹, Xiaolei Shen ¹, Changxiong J. Guo ¹, George E. Hoekel ¹, Yuyan Zhu ², Liang Han ², Kangyun Wu ³, Michael J. Holtzman ³, Qin Liu ¹⁵

¹Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA

²The School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA

³Pulmonary and Critical Care Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA

4These authors contributed equally

https://doi.org/10.1016/j.cell.2024.08.009

Highlights

• Sneezing and coughing are mediated by distinct sensory populations
• Nasal MrgprC11-expressing sensory neurons serve as a core “sneeze” population
• Airway SST-expressing sensory neurons mediate chemically induced cough
• Sneezing and coughing are transmitted and modulated by divergent neuropathways

Summary

Sneezing and coughing are primary symptoms of many respiratory viral infections and allergies. It is generally assumed that sneezing and coughing involve common sensory receptors and molecular neurotransmission mechanisms. Here, we show that the nasal mucosa is innervated by several discrete populations of sensory neurons, but only one population (MrgprC11⁺MrgprA3⁻) mediates sneezing responses to a multitude of nasal irritants, allergens, and viruses. Although this population also innervates the trachea, it does not mediate coughing, as revealed by our newly established cough model. Instead, a distinct sensory population (somatostatin [SST⁺]) mediates coughing but not sneezing, unraveling an unforeseen sensory difference between sneezing and coughing. At the circuit level, sneeze and cough signals are transmitted and modulated by divergent neuropathways. Together, our study reveals the difference in sensory receptors and neurotransmission/modulation mechanisms between sneezing and coughing, offering neuronal drug targets for symptom management in respiratory viral infections and allergies.

Sensory neuronal STAT3 is critical for IL-31 receptor expression and inflammatory itch

Sonoko Takahashi ¹¹³, Sotaro Ochiai ¹¹⁰¹³ Jianshi Jin ²¹¹, Noriko Takahashi ¹, Susumu Toshima ¹³, Harumichi Ishigame ¹¹², Kenji Kabashima ⁴⁵, Masato Kubo ⁶⁷, Manabu Nakayama ⁸, Katsuyuki Shiroguchi ², Takaharu Okada ¹⁹¹⁴

https://doi.org/10.1016/j.celrep.2023.113433

Highlights

• Sensory neuronal IL-31RA and STAT3 are essential for IL-31-induced itch
• STAT3 is important for expression and downstream signaling of IL-31 receptor
• IL-31 enhances GPCR-induced itch transmitted by multiple sensory neuronal subsets
• Sensory neuronal STAT3 contributes to IL-31-independent inflammatory itch

Summary

IL-31 receptor blockade suppresses pruritus of atopic dermatitis. However, cell-type-specific contributions of IL-31 receptor to itch, its expression mechanism, and the downstream signaling pathway to induce itch remain unknown. Here, using conditional knockout mice, we demonstrate that IL-31-induced itch requires sensory neuronal IL-31 receptor and STAT3. We find that IL-31 receptor expression is dependent on STAT3 in sensory neurons. In addition, pharmacological experiments suggest that STAT3 activation is important for the itch-inducing signaling downstream of the IL-31 receptor. A cutaneous IL-31 injection induces the nuclear accumulation of activated STAT3 first in sensory neurons that abundantly express IL-31 receptor and then in other itch-transmitting neurons. IL-31 enhances itch induced by various pruritogens including even chloroquine. Finally, pruritus associated with dermatitis is partially dependent on sensory neuronal IL-31 receptor and strongly on sensory neuronal STAT3. Thus, sensory neuronal STAT3 is essential for IL-31-induced itch and further contributes to IL-31-independent inflammatory itch.

Comprehensive Evaluation of Fourteen Docking Programs on Protein-Peptide Complexes

Gaoqi Weng ¹, Junbo Gao ¹, Zhe Wang ¹, Ercheng Wang ¹, Xueping Hu ¹, Xiaojun Yao ², Dongsheng Cao ³, Tingjun Hou ^1 4

Affiliations expand

• PMID: 32324992
• DOI: 10.1021/acs.jctc.9b01208

Abstract

A large number of protein-protein interactions (PPIs) are mediated by the interactions between proteins and peptide segments binding partners, and therefore determination of protein-peptide interactions (PpIs) is quite crucial to elucidate important biological processes and design peptides or peptidomimetic drugs that can modulate PPIs. Nowadays, as a powerful computation tool, molecular docking has been widely utilized to predict the binding structures of protein-peptide complexes. However, although a number of docking programs have been available, the systematic study on the assessment of their performance for PpIs has never been reported. In this study, a benchmark data set called PepSet consisting of 185 protein-peptide complexes with peptide length ranging from 5 to 20 residues was employed to evaluate the performance of 14 docking programs, including three protein-protein docking programs (ZDOCK, FRODOCK, and HawkDock), three small molecule docking programs (GOLD, Surflex-Dock, and AutoDock Vina), and eight protein-peptide docking programs (GalaxyPepDock, MDockPeP, HPEPDOCK, CABS-dock, pepATTRACT, DINC, AutoDock CrankPep (ADCP), and HADDOCK peptide docking). A new evaluation parameter, named IL_RMSD, was proposed to measure the docking accuracy with f_nat (the fraction of native contacts). In global docking, HPEPDOCK performs the best for the entire data set and yields the success rates of 4.3%, 24.3%, and 55.7% at the top 1, 10, and 100 levels, respectively. In local docking, overall, ADCP achieves the best predictions and reaches the success rates of 11.9%, 37.3%, and 70.3% at the top 1, 10, and 100 levels, respectively. It is expected that our work can provide some helpful insights into the selection and development of improved docking programs for PpIs. The benchmark data set is freely available at http://cadd.zju.edu.cn/pepset/.

Molecular determinants for the chemical activation of the warmth-sensitive TRPV3 channel by the natural monoterpenoid carvacrol

Canyang Niu ¹, Xiaoying Sun ², Fang Hu ², Xiaowen Tang ³, KeWei Wang ⁴

Affiliations expand

• PMID: 35150742
• PMCID: PMC8920929
• DOI: 10.1016/j.jbc.2022.101706

Abstract

Transient receptor potential vanilloid 3 (TRPV3), robustly expressed in the skin, is a nonselective calcium-permeable cation channel activated by warm temperature, voltage, and certain chemicals. Natural monoterpenoid carvacrol from plant oregano is a known skin sensitizer or allergen that specifically activates TRPV3 channel. However, how carvacrol activates TRPV3 mechanistically remains to be understood. Here, we describe the molecular determinants for chemical activation of TRPV3 by the agonist carvacrol. Patch clamp recordings reveal that carvacrol activates TRPV3 in a concentration-dependent manner, with an EC₅₀ of 0.2 mM, by increasing the probability of single-channel open conformation. Molecular docking of carvacrol into cryo-EM structure of TRPV3 combined with site-directed mutagenesis further identified a unique binding pocket formed by the channel S2-S3 linker important for mediating this interaction. Within the binding pocket consisting of four residues (Ile505, Leu508, Arg509, and Asp512), we report that Leu508 is the most critical residue for the activation of TRPV3 by carvacrol, but not 2-APB, a widely used nonspecific agonist and TRP channel modulator. Our findings demonstrate a direct binding of carvacrol to TRPV3 by targeting the channel S2-S3 linker that serves as a critical domain for chemical-mediated activation of TRPV3. We also propose that carvacrol can function as a molecular tool in the design of novel specific TRPV3 modulators for the further understanding of TRPV3 channel pharmacology.

Keywords: 2-APB; TRPV3; amino acid mutation; carvacrol; molecular docking; surface structure.

Vitexin inhibits pain and itch behavior via modulating TRPV4 activity in mice

Zhiqiang Qin ^a1, Lan Xiang ^a1, Siyu Zheng ^a1, Yuchen Zhao ^b, Yanyan Qin ^a, Lei Zhang ^a, Lanlan Zhou ^a

^aSchool of Medical Technology and Nursing, Shenzhen Polytechnic, Shenzhen 518055, China ^bDepartment of Mathematics, University of California, Los Angeles, CA 90095, USA Received 6 March 2023, Revised 27 June 2023, Accepted 28 June 2023, Available online 3 July 2023, Version of Record 3 July 2023.

https://doi.org/10.1016/j.biopha.2023.115101

Abstract
Itching and pain are distinct unpleasant sensations. The transient receptor potential cation channel subfamily V member 4 (TRPV4) pathway is regarded as a shared pathway that mediates pain and itching. Vitexin (Mujingsu, MJS), a C-glycosylflavonoid, is an effective analgesic. This study aimed to explore the antinociceptive and anti-pruritic effects of MJS and whether its effects are mediated via the TRPV4 pathway. Mice were treated with MJS (7.5 mg/kg) 0.5 h prior to the initiation of the pain or itch modeling process. The results showed that MJS suppressed pain-like behavior in hot plate, thermal infiltration, glacial acetic acid twisting, and formalin tests. Administration of MJS decreased the pruritus response induced by histamine, C48/80, chloroquine and BAM8-22 within 30 min. MJS reduced scratching bouts and lessened the wiping reaction of mice under TRPV4 activation by GSK101 (10 µg/5 μl). MJS inhibited scratching behavior in acetone–ether–water (AEW)-treated mice within 60 min. An H1 receptor antagonist—chlorpheniramine (CLP, 400 mg/kg)—and a TRPV4 antagonist—HC067047 (250 ng/kg), exhibited similar effects to those of MJS. Moreover, MJS ameliorated dry skin itch-associated cutaneous barrier disruption in mice. MJS did not inhibit the expression of TRPV4 in the dorsal root ganglion neurons at L2–L3 in AEW mice. These results indicate that the analgesic and anti-pruritic effects of MJS in acute and chronic pain and itching, as well as itching caused by TRPV4 activation, could be attributed to the TRPV4 pathway modulation.

Propionate alleviates itch in murine models of atopic dermatitis by modulating sensory TRP channels of dorsal root ganglion

Yao Xu, Zhuoqiong Qiu, Chaoying Gu, Su Yu, Shangshang Wang, Changlin Li, Xu Yao, Wei Li

First published: 02 January 2024

https://doi.org/10.1111/all.1599

Interpretable bilinear attention network with domain adaptation improves drug–target prediction

Peizhen Bai, Filip Miljković, Bino John & Haiping Lu

Abstract

Predicting drug–target interaction is key for drug discovery. Recent deep learning-based methods show promising performance, but two challenges remain: how to explicitly model and learn local interactions between drugs and targets for better prediction and interpretation and how to optimize generalization performance of predictions on novel drug–target pairs. Here, we present DrugBAN, a deep bilinear attention network (BAN) framework with domain adaptation to explicitly learn pairwise local interactions between drugs and targets, and adapt in response to out-of-distribution data. DrugBAN works on drug molecular graphs and target protein sequences to perform prediction, with conditional domain adversarial learning to align learned interaction representations across different distributions for better generalization on novel drug–target pairs. Experiments on three benchmark datasets under both in-domain and cross-domain settings show that DrugBAN achieves the best overall performance against five state-of-the-art baseline models. Moreover, visualizing the learned bilinear attention map provides interpretable insights from prediction results.

Molecular mechanisms of MrgprA3-independent activation of the transient receptor potential ion channels TRPA1 andTRPV1 by chloroquine

Tabea C Fricke ¹, Sebastian Pantke ¹, Bjarne Lüttmann ¹, Frank G Echtermeyer ¹, Christine Herzog ¹, Mirjam J Eberhardt ¹, Andreas Leffler ¹

Affiliations expand

• PMID: 36928865
• DOI: 10.1111/bph.16072

Abstract

Background and purpose: Itch is associated with several pathologies and is a common drug-induced side effect. Chloroquine (CQ) is reported to induce itch by activating the Mas-related G protein-coupled receptor MrgprA3 and subsequently TRPA1. In this study, we demonstrate that CQ employs at least two MrgprA3-independent mechanisms to activate or sensitize TRPA1 and TRPV1.

Experimental approach: Patch clamp and calcium imaging were utilized to examine effects of CQ on TRPA1 and TRPV1 expressed in HEK 293T cells.

Key results: In calcium imaging, CQ induces a concentration-dependent but MrgprA3-independent activation of TRPA1 and TRPV1. Although CQ itself inhibits TRPA1 and TRPV1 in patch clamp recordings, co-application of CQ and ultraviolet A (UVA) light evokes membrane currents through both channels. This effect is inhibited by the reducing agent dithiothreitol (DTT) and is reduced on mutants lacking cysteine residues accounting for reactive oxygen species (ROS) sensitivity. The combination of CQ and UVA light triggers an accumulation of intracellular ROS, removes fast inactivation of voltage-gated sodium currents and activates TRPV2. On the other hand, CQ is a weak base and induces intracellular alkalosis. Intracellular alkalosis can activate TRPA1 and TRPV1, and CQ applied at alkaline pH values indeed activates both channels.

Conclusion and implications: Our data reveal novel pharmacological properties of CQ, allowing activation of TRPA1 and TRPV1 via photosensitization as well as intracellular alkalosis. These findings add more complexity to the commonly accepted dogma that CQ-induced itch is specifically mediated by MrgprA3 coupling to TRPA1.

Keywords: chloroquine; histamine; itch; oxidative stress; sensory neuron.

© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Satellite Glial Cells and Neurons in Trigeminal Ganglia Are Altered in an Itch Model in Mice

MeytalCohen1,2, RachelFeldman-Goriachnik1,2 and MenachemHanani1,2,*

1 LaboratoryofExperimentalSurgery,Hadassah-HebrewUniversityMedicalCenter,Jerusalem91240,Israel; meytal.cohen@mail.huji.ac.il(M.C.);rahel.gor@gmail.com(R.F.-G.)

2 FacultyofMedicine,TheHebrewUniversityofJerusalem,MountScopus,Jerusalem91240,Israel * Correspondence:hananim@cc.huji.ac.il;Tel.:+972-2-5844721

Abstract: Itch(pruritus) is a common chronic condition with a lifetime prevalence of over 20%. The mechanisms underlying itch are poorly understood,and its therapy is difficult. There is recent evidence that following nerve injury or inflammation, intercellular communications in sensory ganglia are augmented, which may lead to abnormal neuronal activity, and hence to pain, but there is no information on whether such changes take place in an itch model. We studied changes in neurons and satellite glial cells(SGCs)in trigeminal ganglia in an itch model in mice using repeated applications of 2,4,6-trinitro-1-chlorobenzene(TNCB) to the external ear over a period of 11days. Treated mice showed augmented scratching behavior as compared with controls during the application period and for several days afterward.Immunostaining for the activation marker glial fibrillary acidic protein SGCs was greater by about 35% after TNCB application, and gap junction-mediated coupling between neurons increased from about 2% to 13%. The injection of gap junction blockers reduced scratching behavior, suggesting that gap junctions contribute to itch. Calcium imaging studies showed increased responses of SGCs to the pain (and presumed itch )mediator ATP. We conclude that changes in both neurons and SGCs in sensory ganglia may play a role in itch.

Pamoic Acid-Induced Peripheral GPR35 Activation Improves Pruritus and Dermatitis

Chaeeun Kim ¹, Yerin Kim ¹, Ji Yeon Lim ¹, Minseok Kim ¹, Haiyan Zheng ¹, Miri Kim ¹, Sun Wook Hwang ¹

Affiliations expand

• PMID: 37501600
• DOI: 10.1111/bph.16201

Abstract

Background and purpose: Pruritic dermatitis is a disease with a considerable unmet need for treatment and appears to present with not only epidermal but also peripheral neuronal complications. Here we propose a novel pharmacologic modulation targeting both peripheral dorsal root ganglion (DRG) sensory neurons and skin keratinocytes. GPR35 is an orphan G-protein-coupled receptor expressed in DRG neurons and has been predicted to downregulate neuronal excitability when activated. Modulator information is currently increasing for GPR35 and pamoic acid (PA), a salt-forming agent for drugs, has been shown to be an activator solely specific for GPR35. Here we investigated its effect on dermatitic pathology.

Experimental approach: We confirmed GPR35 expression in peripheral neurons and tissues. The effect of PA treatment was pharmacologically evaluated in cultured cells in vitro and in in vivo animal models for acute and chronic pruritus.

Key results: Local PA application mitigated acute non-histaminergic itch and consistently, obstructed DRG neuronal responses. Keratinocyte fragmentation under dermatitic simulation was also dampened following PA incubation. Chronic pruritus in 1-chloro-2,4-dinitrobenzene (DNCB) and psoriasis models was also moderately but significantly reversed by the repeated applications of PA. Dermatitic scores in the DNCB and psoriatic models were also improved by its application, indicating that it is beneficial for mitigating disease pathology.

Conclusions and implications: Our findings suggest that pamoic acid activation of peripheral GPR35 can contribute to the improvement of pruritus and its associated diseases.

Keywords: GPR35; Pamoic acid; dermatitis; itch; neuron.