삼환계 항우울제의 오피오이드 수용체 자극에 의한 TRPC4 이온통로의 활성 연구

Abstract

The transient receptor potential canonical 4 (TRPC4) ion channel is a non-selective cation channel involved in cellular electrical signaling and homeostasis. It plays a crucial role in various physiological processes, including neurotransmission, cellular growth, and cardiovascular function. The activation of TRPC4 is influenced by its interaction with G protein-coupled receptors (GPCRs), particularly through the Gi signaling pathway. In this study, we aimed to investigate the interplay between TRPC4 and opioid receptor modulation, with a specific focus on the impact of tricyclic antidepressants (TCAs). TCAs are widely used in the treatment of depressive disorders and are known to modulate opioid receptors. However, the precise mechanisms underlying their effects on TRPC4 ion channel activity remain unclear. Our results demonstrate that TRPC4 activity is dependent on the Gi signaling pathway, indicating the involvement of intracellular signaling in TRPC4 gating. Furthermore, we observed that perturbation of Gi protein function or mutation of key residues within TRPC4 impairs its activation by TCAs and opioid receptor agonists. This suggests that TRPC4 ion channel activity is regulated by the Gi signaling pathway and can be modulated by TCA treatment. Importantly, the bidirectional effects of TCAs on TRPC4 activity, depending on their concentration and opioid receptor modulation, raise questions about the potential signaling complexities and the underlying mechanisms contributing to the side effects associated with TCA therapy.Overall, our findings highlight the intricate relationship between TRPC4 ion channel activity, Gi signaling pathway, and opioid receptor modulation, emphasizing the role of TCAs in this interplay. Understanding the regulatory mechanisms of TRPC4 and its modulation by TCAs and opioid receptors provides valuable insights for the development of novel therapeutic strategies targeting TRPC4 for conditions such as depression, neuropathic pain, and other TRPC4-related disorders.