G protein-coupled receptors (GPCRs) are crucial sensory integral membrane proteins. Earlier structural and biophysical studies focused on elucidating mechanisms of receptor−ligand and receptor−protein molecular recognition, specifically how extracellular ligands and intracellular signaling partners engaged the receptor [1, 2, 3]. More recently, attention has shifted toward the integral role of the membrane environment itself, particularly how lipid-receptor interactions modulate ligand binding and agonist-induced signaling [4]. A growing body of structural and functional evidence supports the view that lipids can profoundly influence GPCR activity, not only as allosteric or orthosteric modulators, but also through bulk membrane properties such as curvature [5] and fluidity. Insights into GPCR-lipid interactions provide a critical framework for bridging in vitro structural and pharmacological observations with the receptor's physiological functions in vivo.

NMR spectroscopy has a long-standing history studying biological membranes and lipid–protein interactions, with pioneering investigations of lipid bilayers dating back over five decades [6, 7, 8]. More recently, NMR has emerged as a powerful tool for elucidating the mechanisms of G protein-coupled receptor (GPCR) signaling by enabling the observation of multiple conformational states in equilibrium and revealing how small-molecule ligands modulate these conformational landscapes, as has been reviewed [9, 10, 11, 12, 13]. Important advantages of NMR include the flexibility to study membrane proteins in a wide range of membrane or membrane-mimetic systems and at physiologically relevant temperature. GPCR studies have increasingly leveraged these strengths to uncover new mechanistic insights into how lipids and biological membranes influence receptor conformational equilibria.

This review highlights recent contributions from NMR spectroscopy to our current understanding of how biological membranes and lipids influence GPCR signaling. We discuss NMR studies that directly probe GPCRs as well as investigations into the effects of membrane environments on GPCR interactions with their partner signaling proteins. Examples from the literature illustrate the application of diverse NMR methodologies, including 19F NMR and multi-dimensional experiments enabled by various stable-isotope labeling strategies. Insights derived from both solid-state and solution NMR approaches are discussed, with an emphasis on unique strengths of each method. Collectively, these studies underscore how NMR has advanced our molecular understanding of GPCR function by revealing how specific lipid species and bulk membrane properties influence receptor activation, modulate interactions with effector proteins, and affect the interpretation of GPCR activity in membrane mimetic systems.