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Papers of the Week

Papers: 6 May 2023 - 12 May 2023

Basic Science

In Vitro Studies, Pharmacology/Drug Development

2023 May 08

Am J Physiol Cell Physiol


Low concentrations of tricyclic antidepressants stimulate TRPC4 channel activity by acting as an opioid receptor ligand.


Jeong B, Song YP, Chung JY, Park KC, Kim JH, So I, Hong C


Traditionally prescribed for mood disorders, tricyclic antidepressants (TCAs) have shown promising therapeutic effects on chronic neuralgia and irritable bowel syndrome. However, the mechanism by which these atypical effects manifest is unclear. Among the proposed mechanisms is the well-known pain-related inhibitory G-protein coupled receptor (GPCR), namely, the opioid receptor (OR). Here, we confirmed that TCA indeed stimulates OR and regulates the gating of TRPC4, a downstream signaling of the G-pathway. In an ELISA to quantify the amount of intracellular cAMP, a downstream product of OR/G-pathway, treatment with amitriptyline (AMI) showed a decrease in [cAMP] similar to that of the μOR agonist. Next, we explored the binding site of TCA by modeling the previously revealed ligand-bound structure of μOR. A conserved aspartate residue of ORs was predicted to participate in salt bridge interaction with the amine group of TCAs, and in aspartate-to-arginine mutation, AMI did not decrease the FRET-based binding efficiency between the ORs and Gα. As an alternative way to monitor the downstream signaling of G-pathway, we evaluated the functional activity of TRPC4 channel, as it is well known to be activated by Gα. TCAs increased the TRPC4 current through ORs, and TCA-evoked TRPC4 activation was abolished by an inhibitor of Gα or its dominant-negative mutant. As expected, TCA-evoked activation of TRPC4 was not observed in the aspartate mutants of OR. Taken together, OR could be proclaimed as a promising target among numerous binding partners of TCA, and TCA-evoked TRPC4 activation may help to explain the nonopioid analgesic effect of TCA.