대장 평활근의 TRPC4 이온통로 억제를 통한 삼환계 항우울제의 소화기 운동성 조절기전 연구

Abstract

Tricyclic antidepressants (TCAs) have been used to treat depression, however, side effects were reported in the central nervous system, cardiovascular, and reproductive system, making it difficult to prescribe. Recently, TCA has emerged as a treatment for irritable bowel syndrome (IBS) based on its analgesic effect and constipation symptom among side effects. However, the molecular mechanism of TCAs effect in IBS treatment poorly understood. Transient receptor potential channel canonical type 4 (TRPC4) which is Ca2+-permeable non-selective cation channel, is proposed as target molecules for the mechanism of TCAs. Herein, I investigated whether TCAs modulate TRPC4 channel activity. To determine the contribution of TRPC4 to colonic motility, I measured the electrical activity of heterologous or endogenous TRPC4 by TCAs using the patch clamp technique in HEK293 cells and murine colonic myocytes. In TRPC4-overexpressed HEK293 cells, I observed TCA-evoked direct inhibition of TRPC4. Compared with TRPC4-knockout mice, I identified that muscarinic cationic current (mIcat) was suppressed through TRPC4 inhibition by TCA in isolated murine colonic myocytes. Collectively, I suggested that TCA action is responsible for the inhibition of TRPC4 channels in colonic myocytes, ultimately causing constipation. These findings provide clinical insights into abnormal intestinal motility and medical interventions aimed at IBS therapy.