Biophysical Society Thematic Meeting | Bucharest 2026

Biophysics of Membrane Reactions in Brian

Monday Speaker Abstracts

SPECTROSCOPIC INSIGHTS INTO THE MOLECULAR MECHANISMS UNDERLYING BIASED GPCR SIGNALING Kota Katayama 1,2 ; 1 Nagoya Institute of Technology, Life Science and Applied Chemistry, Nagoya, Japan 2 Nagoya Institute of Technology, OptoBioTechnology Research Center, Nagoya, Japan Opioid analgesics exert potent pain-relieving effects by activating opioid receptors, a class of G protein–coupled receptors (GPCRs) and remain indispensable for the management of severe pain associated with cancer and other conditions. However, their clinical use is limited by serious adverse effects, including tolerance and dependence. Consequently, there is a strong demand for the rational development of next-generation opioid drugs based on structural and mechanistic insights into opioid receptor signaling, although this effort is challenged by the complexity of receptor-mediated intracellular signaling pathways. Opioid receptor signaling involves at least two major pathways: G protein–mediated and arrestin-mediated signaling. While the former is generally associated with analgesic effects, activation of the latter has been linked to adverse effects, motivating the development of “biased” ligands that selectively modulate specific signaling pathways. Despite extensive efforts, the molecular mechanisms underlying signaling bias in opioid receptors—and GPCRs more broadly—are not yet fully understood. Recent studies have suggested that endogenous sodium ions play a critical role in regulating GPCR signaling bias. Nevertheless, direct observation of sodium ion binding within the receptor has been technically challenging, thereby limiting mechanistic understanding of this phenomenon. In this work, we employ an infrared spectroscopic approach developed in our laboratory to investigate the molecular differences between G protein– and arrestin-mediated signaling pathways in opioid receptors. By measuring ligand- and sodium ion–induced infrared difference spectra of opioid receptors bound to biased agonists and various ligands, we capture subtle changes in molecular interactions that are difficult to detect using conventional structural biology methods alone. In this presentation, we discuss how these spectroscopic signatures provide new insights into the molecular basis of signaling bias in opioid receptors and offer a framework for understanding biased signaling across the GPCR family.

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