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Last update 08 May 2025

CLCA1

Last update 08 May 2025

Basic Info

Synonyms

CaCC, CaCC-1, CACC1

+ [8]

Introduction

May be involved in mediating calcium-activated chloride conductance. May play critical roles in goblet cell metaplasia, mucus hypersecretion, cystic fibrosis and AHR. May be involved in the regulation of mucus production and/or secretion by goblet cells. Involved in the regulation of tissue inflammation in the innate immune response. May play a role as a tumor suppressor. Induces MUC5AC.

Drugs associated with CLCA1

VS-002

Target

CFTR x CLCA1 x NHE3

Mechanism

CFTR inhibitors [+2]

Active Org.

Nuvara Therapeutics

Originator Org.

Nuvara Therapeutics

Active Indication

Diarrhea

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

HG-1011

Target

CLCA1

Mechanism

CLCA1 modulators

Active Org.-

Originator Org.

Human Genome Sciences, Inc.

Active Indication-

Inactive Indication

Immune System Diseases [+3]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with CLCA1

100 Translational Medicine associated with CLCA1

0 Patents (Medical) associated with CLCA1

234

Literatures (Medical) associated with CLCA1

01 May 2025·American Journal of Physiology-Gastrointestinal and Liver Physiology

Hypobaric hypoxia exposure impairs colonic goblet cell subpopulation via the HIF-1α signaling pathway

Article

Author: Zhu, Lingling ; Hu, Yazhuo ; Liu, Jing ; Jiang, Xiufang ; Gao, Jiayue ; Cheng, Xiang ; Meng, Fansen ; Zhao, Tong ; Wang, Gangshi ; Zhang, Shaojie ; Zhang, Wangjingyi

We investigated the role of hypoxia-inducible factor-1α (HIF-1α) in colonic goblet cell injury under hypobaric hypoxia exposure. Our results indicate that the elevation of HIF-1α caused by hypobaric hypoxia exposure can significantly reduce canonical goblet cells and disrupt intestinal mucosal barrier function. It provides a potential intervention strategy for restoring goblet cell function under hypobaric hypoxic conditions.

01 Apr 2025·Journal of Advanced Research

Blockade of calcium-activated chloride channel ANO1 ameliorates ionizing radiation-induced intestinal injury

Article

Author: Yuan, Tong ; Wang, Yuna ; Xia, Lei ; Guo, Yuying ; Zhang, Junling ; Fan, Saijun

INTRODUCTIONRadiation enteritis is one of the most frequent clinical complications of radiotherapy (RT), yet few effective strategies currently exist to protect against that. Anoctamin 1 (ANO1) functions both as a chloride channel and a signal transduction protein, influencing numerous pathophysiological processes.OBJECTIVESThis study aimed to investigate whether targeting ANO1 could mitigate radiation-induced enteritis while enhancing tumor radiosensitivity.METHODSQuantitative PCR (qPCR) and Western blot (WB) were used to assess ANO1 expression and its changes after irradiation. Survival rates were recorded to evaluate the effects of ANO1 agonist and inhibitors. A cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor was administered to irradiated mice to investigate the role of chloride channel in radiation protection. qPCR and WB were executed to analyze the expression of relevant ion channels in intestinal epithelium. Functional validation was conducted using inhibitors in mice and 3D organoids. Fluorescent probe kits detected intracellular ion levels and membrane potential, and WB was performed to elucidate the underlying mechanisms. Finally, the radiosensitizing effect of CaCCinh-A01 was assessed in colorectal cancer (CRC) cells and validated in in vivo models.RESULTSBlocking the calcium-activated chloride channel (CaCC) protein ANO1, which is highly expressed in the colon, protects the intestine from radiation-induced damage. The ANO1 inhibitor CaCCinh-A01, suppresses CaCC currents, downregulates ANO1 protein expression, alleviates radiation-induced intestine injury, and enhances the radiosensitivity of CRC. Mechanistically, CaCCinh-A01 upregulates Na-K-Cl Cotransporter 1 (NKCC1) protein expression, leading to an increase in intracellular Cl^- concentration and the inhibition of membrane depolarization in MODE-K cells. This subsequently inhibits p53-mediate DNA damage signaling, ultimately alleviating ionizing radiation-induced intestinal injury.CONCLUSIONThese findings suggest that targeting ANO1 not only alleviates radiation-induced intestinal injury in mice but also enhances CRC radiosensitivity. Thus, ANO1 represents a promising therapeutic target for mitigating the side effects of RT in CRC patients.

09 Jan 2025·JCI Insight

The CLCA1/TMEM16A/Cl– current axis associates with H2S deficiency in diabetic kidney injury

Article

Author: Lee, Hak Joo ; Zhang, Guanshi ; Singh, Brij B ; Sun, Yuyang ; Kasinath, Balakuntalam S ; Kevil, Christopher G ; Ju, Wenjun ; Nelson, Robert G ; Sharma, Kumar ; Ghosh Choudhury, Goutam ; Kretzler, Matthias ; Das, Falguni ; Nair, Viji ; Varadarajan, Shankara

The role played by anionic channels in diabetic kidney disease (DKD) is not known. Chloride channel accessory 1 (CLCA1) facilitates the activity of TMEM16A (Anoctamin-1), a Ca2+-dependent Cl- channel. We examined if CLCA1/TMEM16A had a role in DKD. In mice with type 2 diabetes, renal cortical CLCA1 and TMEM16A content was increased. CLCA1 and TMEM16A content was associated with hydrogen sulfide (H2S) deficiency, mTOR complex 1 (mTORC1) activation, albuminuria, and matrix increase. Administering sodium hydrosulfide (NaHS), a source of H2S, mitigated these changes. In proximal tubular epithelial (MCT) cells, high glucose rapidly increased CLCA1 by recruiting the IL-6/STAT3 axis and augmented TMEM16A expression by stimulating its mRNA translation; these changes were abolished by NaHS. Patch clamp experiments showed that high glucose increased Cl- current in MCT cells that was ameliorated by NaHS and a TMEM16A chemical inhibitor. siRNA against CLCA1 or TMEM16A and TMEM16A inhibitor abolished high glucose-induced mTORC1 activation and matrix protein increase. Tubular expression of TMEM16A correlated with albuminuria in kidney biopsies from people with type 2 diabetes. We report a pathway for DKD in which H2S deficiency results in kidney injury by the recruitment of the CLCA1/TMEM16A/Cl- current system.

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CLCA1

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