Antidepressants interact with an LPA₃ receptor binding site: Functional and docking studies.

Area of Science:

• Pharmacology
• Molecular Biology
• Neuroscience

Background:

• Lysophosphatidic acid receptors (LPARs) are G protein-coupled receptors involved in various physiological processes.
• LPA3 receptors, specifically, have been implicated in cellular signaling pathways relevant to neurological functions.
• Understanding how common pharmaceuticals interact with these receptors is crucial for drug development and therapeutic strategies.

Purpose of the Study:

• To investigate the effects of commonly prescribed antidepressants (imipramine, amitriptyline, paroxetine) on the lysophosphatidic acid receptor 3 (LPA3).
• To elucidate the molecular mechanisms underlying these interactions using both cellular assays and computational modeling.
• To explore the potential therapeutic implications of these findings in the context of antidepressant action.

Main Methods:

• Cellular assays using receptor-transfected HEK 293 Flp-In TREx cells to assess receptor activity.
• Measurement of intracellular calcium levels and ERK 1/2 phosphorylation in response to drug treatment.
• In silico molecular docking simulations to predict drug-receptor interactions within the LPA3 binding pocket.

Main Results:

• Antidepressants exhibited low affinity and efficacy at LPA3 receptors compared to the natural ligand LPA.
• Paroxetine increased intracellular calcium, while imipramine and amitriptyline decreased it; imipramine also potently increased ERK 1/2 phosphorylation.
• These cellular effects were dependent on LPA3 receptor expression and involved distinct amino acid interactions within the receptor's Upper Cavity, leading to receptor internalization and morphological changes.

Conclusions:

• Imipramine, amitriptyline, and paroxetine modulate LPA3 receptor activity, influencing key intracellular signaling pathways.
• The observed effects on calcium and ERK phosphorylation are LPA3-dependent, highlighting the receptor's role in mediating antidepressant actions.
• These findings provide novel insights into the molecular mechanisms of antidepressants and suggest potential therapeutic avenues targeting the LPA3 receptor.