Tricyclic antidepressants dose-dependently modulate the biphasic activity of the TRPC5 channel through opioid receptors

• 발행기관: 대한생리학회-대한약리학회
• 간행물 정보: 『The Korean Journal of Physiology & Pharmacology』제29권 제4호, 455~464쪽, 전체 10쪽
• 주제분류: 의약학 > 의학일반
• 파일형태: PDF
• 발행일자: 2025.06.30

국문 초록

Tricyclic antidepressants (TCAs) have been widely used for the treatment of major depressive disorder and other psychiatric conditions. However, their clinical application has declined due to adverse side effects and the availability of newer antidepressants with improved safety profiles. TCAs primarily target serotonin and norepinephrine receptors but also interact with a variety of other receptors and ion channels, contributing to both their therapeutic and adverse effects. We previously reported that TCAs regulate transient receptor potential canonical type 4 (TRPC4) channels. In this study, we investigated whether TCAs similarly modulate TRPC5 channels. Using HEK293 cells overexpressing TRPC5, we measured TRPC5 currents and intracellular calcium levels. Without altering TRPC5 expression levels, TCAs (amitriptyline, desipramine, and imipramine) dose-dependently reduced inward currents through TRPC5, with IC?? values of 2.9, 10.3, and 11.7 μM, respectively. Given that TCAs can act as off-target agonists at opioid receptors (ORs), we co-expressed TRPC5 with various OR subtypes (μ-, δ-, and κ-ORs). Our results revealed that at low concentrations, TCAs enhanced TRPC5 activation through OR stimulation, whereas at higher concentrations, competitive inhibition of TRPC5 activity predominated. The biphasic modulation of TRPC5 by TCAs may contribute to a wide spectrum of cardiovascular and neurological manifestations, depending on the dosage and clinical application. Overall, these findings enhance the pharmacological understanding of the molecular mechanisms underlying the actions of TCAs and emphasize the need for more targeted therapeutic approaches.

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키워드

Biphasic Depression Opioid receptor Tricyclic antidepressant TRPC5