Colonic overexpression of the T-type calcium channel Cav3.2 in a mouse model of visceral hypersensitivity and in irritable bowel syndrome patients

Abstract

Background

Among the different mechanisms involved in irritable bowel syndrome (IBS) physiopathology, visceral hypersensitivity seems to play a key role. It involves sensitization of the colonic primary afferent fibers, especially through an overexpression of ion channels. The aims of this translational study were to investigate the colonic expression of Ca_v3.2 calcium channels and their involvement in an animal model of colonic hypersensitivity, and to assess their expression in the colonic mucosa of symptomatic IBS patients.

Methods

This bench-to-bed study combined a preclinical experimental study on mice and a case–control clinical study. Preclinical studies were performed on wild-type and Ca_v3.2-KO mice. Colonic sensitivity and Ca_v3.2 expression were studied after a low-dose treatment of dextran sodium sulfate (DSS 0.5%). Regarding the clinical study, colonic biopsies were performed in 14 IBS patients and 16 controls during a colonoscopy to analyze the mucosal Ca_v3.2 expression.

Key results

Wild-type, but not Ca_v3.2-KO, mice developed visceral hypersensitivity without colonic inflammation, after 0.5% DSS treatment. A significant increase of Ca_v3.2 mRNA (p = 0.04) was found in the colon of low-dose DSS-treated wild-type (WT) mice compared to their controls. In human colonic biopsies, the Ca_v3.2 mRNA level was significantly higher in the IBS group compared to the control group (p = 0.01). The immunofluorescence staining revealed their protein expression in colonic mucosa, particularly in nerve fibers.

Conclusions & inferences

This translational study supports the involvement of the calcium channels Ca_v3.2 in abdominal pain, as observed in IBS patients. It opens new therapeutic perspectives based on molecules specifically blocking these channels.

Our work is a bench-to-bed approach to visceral hypersensitivity in irritable bowel syndrome (IBS). We performed preclinical studies on wild-type and Cav3.2-deficient (Cav3.2-KO) mice, in which visceral hypersensitivity has been induced using 0.5% DSS, showing that the T-type calcium channel Cav3.2 is involved in visceral hypersensitivity. We conducted a prospective clinical study on colonic biopsies from 14 IBS patients and 16 healthy controls, revealing that Cav3.2 calcium channel is overexpressed in colonic biopsies of IBS patients, compared to controls. Thus, Cav3.2 channels could represent a new interesting target to improve IBS patients' abdominal pain.

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