Inhibition of TRPC4 channel activity in colonic myocytes by tricyclic antidepressants disrupts colonic motility causing constipation

Abstract

Tricyclic antidepressants (TCAs) have been used to treat depression and were recently approved for treating irritable bowel syndrome (IBS) patients with severe or refractory IBS symptoms. However, the molecular mechanism of TCA action in the gastrointestinal (GI) tract remains poorly understood. Transient receptor potential channel canonical type 4 (TRPC4), which is a Ca2+‐permeable nonselective cation channel, is a critical regulator of GI excitability. Herein, we investigated whether TCA modulates TRPC4 channel activity and which mechanism in colonic myocytes consequently causes constipation. To prove the clinical benefit in patients with diarrhoea caused by TCA treatment, we performed mechanical tension recording of repetitive motor pattern (RMP) in segment, electric field stimulation (EFS)‐induced and spontaneous contractions in isolated muscle strips. From these recordings, we observed that all TCA compounds significantly inhibited contractions of colonic motility in human. To determine the contribution of TRPC4 to colonic motility, we 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 HEK cells, we observed TCA‐evoked direct inhibition of TRPC4. Compared with TRPC4‐knockout mice, we identified that muscarinic cationic current (mIcat) was suppressed through TRPC4 inhibition by TCA in isolated murine colonic myocytes. Collectively, we suggest 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.

Central Neuromodulators in Irritable Bowel Syndrome: Why, How, and When

“…The antimuscarinic effect of TCAs is associated with constipation due to decreased intestinal motility. This condition can also be related to the inhibitory action of these agents on transient receptor potential channel canonical type 4 in colonic myocytes that disrupt colonic motility ( 6 , 28 ).…”

“…In addition, like some of the TCAs, it has 5-HT2A and 5-HT2C receptor antagonist properties, which may account for some additional antidepressant properties, as well as a more favorable side effect profile by blocking some of the unwanted receptor actions of boosting 5-HT transmission (6,29). The same applies to its 5-HT3 antagonist properties, which may explain its more favorable GI side effect profile, including reduced nausea, pain, and diarrhea, although this same mechanism could induce constipation (6,20,28). Likewise, through its H1 and 5-HT2C antagonist properties, mirtazapine may cause increased appetite, weight gain, sedation, fatigue, sweating, and dry mouth (6,30,39,41).…”

Inhibitory Action of the General Anesthetic Ketamine on Intracellular Calcium Transients and Smooth Muscle Contractions of the Mouse Small Intestine

“…Водночас важливо, що використовувані у медицині антидепресанти та анестетики мають побічну дію на TRP-канали. Було показано, що трициклічні антидепресанти інгібували TRPC4-канали у міоцитах товстої кишки, що в результаті викликало пригнічення моторики [24]. Ці дані збігаються з нашими нещодавніми результатами дослідження, які демонструють інгібуючу дію анестетика кетаміну та ізофлурану на опосередкований TRPC4-каналами мускариновий катіонний струм міоцитів тонкої кишки миші [7,13]…”

General anaesthesia-related complications of gut motility with a focus on cholinergic mechanisms, TRP channels and visceral pain

“…Currently, the most effective and widely used treatments for post-traumatic stress disorder (PTSD) are antidepressants and anxiolytics, but other novel treatments are being considered, especially for the treatment of more refractory and disabling cases of PTSD ( Ipser and Stein, 2012 ; Liriano et al, 2019 ). Thus, ketamine is not only a widely used anesthetic, but has recently been considered as a potential antidepressant ( Duman et al, 2012 ; Zanos and Gould, 2018 ; Jeong et al, 2022 ), in particular as a promising and novel pharmacotherapeutic agent for PTSD patients, especially in more complex cases ( Liriano et al, 2019 ).…”

“…Antidepressants, in turn, affect TRP channels, and not only in the nervous system, but also in other systems and organs, where they can produce side effects. It was shown that tricyclic antidepressants, which are also used for treating IBS, inhibited TRPC4 channels in colonic myocytes, resulting in suppression of GI motility ( Jeong et al, 2022 ). These results well correlate with our recent studies of the inhibitory action of ketamine and isoflurane on the TRPC4 channel-mediated mI CAT in mouse small intestinal myocytes ( Dryn et al, 2018 ; Melnyk et al, 2020 ).…”