Calcium-activated chloride channel regulator 1 (CLCA1): More than a regulator of chloride transport and mucus production

Cong-Lin Liu; Guo-Ping Shi

doi:10.1016/j.waojou.2019.100077

Calcium-activated chloride channel regulator 1 (CLCA1): More than a regulator of chloride transport and mucus production

World Allergy Organ J. 2019 Nov 29;12(11):100077. doi: 10.1016/j.waojou.2019.100077. eCollection 2019 Nov.

Authors

Cong-Lin Liu^{1

2}, Guo-Ping Shi^{1

2}

Affiliations

¹ Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
² Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.

Abstract

CLCA1 is a member of the CLCA (calcium-activated chloride channel regulator) family and plays an essential role in goblet cell mucus production from the respiratory tract epithelium. CLCA1 also regulates Ca²⁺-dependent Cl^- transport that involves the channel protein transmembrane protein 16A (TMEM16A) and its accessary molecules. CLCA1 modulates epithelial cell chloride current and participates in the pathogenesis of mucus hypersecretory-associated respiratory and gastrointestinal diseases, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonia, colon colitis, cystic fibrosis intestinal mucous disease, ulcerative colitis, and gastrointestinal parasitic infection. Most studies have been focused on the expression regulation of CLCA1 in human specimens. Limited studies used the CLCA1-deficient mice and CLCA1 blocking agents and yielded inconsistent conclusions regarding its role in these diseases. CLCA1 not only regulates mucin expression, but also participates in innate immune responses by binding to yet unidentified molecules on inflammatory cells for cytokine and chemokine production. CLCA1 also targets lymphatic endothelial cells and cancer cells by regulating lymphatic cell proliferation and lymphatic sinus growth in the lymphatic organs and controlling cancer cell differentiation, proliferation, and apoptosis, all which depend on the location of the lymphatic vessels, the type of cancers, the presence of Th2 cytokines, and possibly the availability and type of CLCA1-binding proteins. Here we summarize available studies related to these different activities of CLCA1 to assist our understanding of how this secreted modifier of calcium-activated chloride channels (CaCCs) affects mucus production and innate immunity during the pathogenesis of respiratory, gastrointestinal, and malignant diseases.

Keywords: AMCase, acidic mammalian chitinase; BALF, bronchoalveolar lavage fluid; Bpifa1, bactericidal/permeability-increasing protein (BPI) fold-containing family A member 1; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; CLCA1; CLCA1, calcium-activated chloride channel regulator 1; COPD, chronic obstructive pulmonary disease; CXCL-1, C-X-C motif chemokine ligand 1; CaCCs, calcium-activated chloride channels; Cancer; CeO2NPs, cerium dioxide nanoparticles; DOG1, discovered on gastrointestinal stromal tumours-1; DSS, dextran sodium sulfate; EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transition; ERK, extracellular signal-regulated kinase; EpOCs, epithelial organoid cultures; FAK, focal adhesion kinase; Gastrointestinal disease; Gob-5, goblet cell protein-5; HDMA, house dust mite allergen; IAD, inflammatory airway diseases; Innate immunity; KCNMB1, potassium calcium-activated channel subfamily M regulatory beta subunit 1; LFA-1, lymphocyte function-associated antigen 1.; LFC, log2 fold change; MUC5AC, mucin 5AC; Mucin; NFA, niflumic acid; OVA, ovalbumin; Respiratory diseases; SPDEF, sterile alpha motif [SAM] domain-containing prostate-derived Ets transcription factor; STAT6, signal transducer and activator of transcription 6; TMEM16A, transmembrane protein 16A; TNF-α, tumor necrosis factor-α; VWA, von Willebrand factor type A; WT, wild-type; cAMP, cyclic adenosine monophosphate; rIFABP, rat intestinal fatty acid binding protein promoter; β4BMs, β4-binding motifs.