Grant: Discovery Grants Program - Individual

Membrane potential is one of the defining characteristics of living cells. Recent work has shown that membrane potential modulates signal transduction and ligand binding in G protein-coupled receptors (GPCRs). As it may enable differential signaling patterns depending on tissue, cell type, and excitation state of excitable cells, the voltage sensitivity of GPCRs could have important implications for their pharmacology. Voltage-gated sodium channels (VGSCs) are the primary ion channels for neuronal excitability, crucial for resting potential and generating and propagating action potentials in neurons. Our work on allosteric control of opioid receptors by Na+ highlighted a critical role in regulating the activity of GPCR directly. Still, unexpectedly, it also revealed a significant contribution of membrane potential in the observed effects. Thus, changes in intracellular sodium levels and membrane potential can modulate the activity of opioid receptors and subsequently impact the cellular responses to opioids and other GPCR ligands. Our data support the hypothesis that local Na+ concentration, as well as membrane potential, are critical to the overall biased response of opioid receptor ligands that could explain the heterogeneity of drug response and unpredictable side effect profile. Understanding these interconnected mechanisms is crucial for the development of more effective and safer opioid-based medications and for gaining insights into the development of alternative pharmacotherapy exploiting voltage dependence, such as bifunctional ligands dually targeting opioid receptors and VGSCs. Herein, we propose to study (Aim1) and exploit (Aim2) this interconnectivity. Aim 1 - Study of the effect of Na+ concentration and voltage dependence of opioid receptors as well as the ligand dependency of the observed effects. The mechanistic independence of the opioid and Nav1.7 system allows combinational therapy. But for this, it is important to understand better the impact of membrane potential and Na+ concentration on opioid receptor signaling and study the ligand-dependency of this effect. Aim 2- Functionally characterizing MOR ligand dually targeting the MOR and Nav1.7. The proposed synthetic hybrid drugs comprise two moieties targeting MOR and a second pain target, Nav1.7, connected via a suitable linker. The MOR pharmacophore, derived from either PZM21 or fentanyl, anchors the ligand in the MOR and generates most of the agonistic effect. The proposed research aligns well with my long-term research program, which revolves around three pillars: 1- Understanding opioid receptor signaling and regulation; 2- Developing tools for drug discovery for G protein-coupled receptors and ion channels; 3- Studying the interrelation between GPCRs and ion channels. Our research will guide us towards a better rational design of alternative pharmacotherapies for treating pain-related diseases without significant drawbacks.