G protein–coupled receptors (GPCRs) constitute the largest and most versatile family of membrane proteins in eukaryotes, mediating signal transduction in virtually every physiological process. The conceptual foundation of GPCR research can be traced back to the early 20th century, when the “hormone–receptor” theory proposed that key hormones such as adrenaline elicit their biological effects through specific cellular receptors. This conceptual framework was experimentally substantiated in the 1970s by the pioneering work of Robert Lefkowitz, who employed radiolabeled ligand-binding assays to identify or isolate the ACTH receptor and adrenergic receptor—demonstrating for the first time that hormone receptors are indeed discrete protein entities of approximately 65 kDa [1], [2], [3], [4]. This landmark discovery laid the biochemical groundwork for modern receptor biology. The subsequent advent of molecular cloning technology revolutionized the field. In 1986, Lefkowitz and Brian Kobilka successfully cloned the β2-adrenergic receptor gene, revealing that its polypeptide chain contains seven hydrophobic transmembrane segments. This seminal discovery established the unifying concept that members of the GPCR superfamily may share a characteristic seven-transmembrane (7TM) helical architecture [5], [6]. Mechanistically, activation of GPCRs will recruit G protein trimer and then promote dissociation of Gα from GβGγ, to regulate intracellular second messenger levels, including cAMP and IP3/DAG [7], [8], [9]. These receptors were then phosphorylated by GRKs [10], [11], which induce recruitment of different arrestin subtypes [12], [13], [14], [15], to mediate receptor desensitization (Gα signaling) desensitization or initiate G protein independent signaling [16], [17], [18], [19], [20], [21]. Yet, despite this conceptual breakthrough, the structural elucidation of GPCRs remained elusive for decades due to their intrinsic instability and the technical challenges associated with membrane protein crystallization. Only the rhodopsin structure was available for nearly two decades [22]. A major turning point came with the work of Brian Kobilka and colleagues, who in 2007 resolved the high-resolution crystal structure of the β2-adrenergic receptor by developing lysozyme insertion method [23], and later, in 2011, captured its active-state complex with the G protein [24]. These achievements provided a series of atomic-level insights into the mechanism of GPCR-mediated signal transduction. In the past decade, transformative advances in cryo–electron microscopy (cryo-EM) have further accelerated structural studies. These advances enable the visualization of GPCRs in complex with a variety of downstream effectors, including G proteins and arrestins, thus illuminating the dynamic conformational landscape that governs GPCR signaling and regulation. On the pharmacological front, Lefkowitz further shaped the field by introducing the ternary complex model, elucidating the molecular basis of receptor desensitization, and proposing the G protein/arrestin signaling bias paradigm, each of which has had profound and lasting impact on modern receptor pharmacology [25], [26], [27].

GPCRs function as essential molecular hubs that sense extracellular cues and initiate transmembrane signaling, thereby governing diverse physiological processes ranging from hormonal responses to sensory perception. Many GPCR members have a natural/orthosteric ligand-binding pocket located in the upper region of the seven transmembrane (7TM) bundle, providing a structurally stable and readily accessible site for small-molecule modulation. The intrinsic conformational plasticity of GPCRs enables ligands to fine-tune receptor activity through allosteric modulation of downstream effectors coupling to the cytoplasmic side of the receptor [28]. In addition, the highly tissue- and cell-type-specific expression patterns of GPCRs offer a strong theoretical basis for the development of selective therapeutics with minimal off-target effects [29].

Despite the fact that GPCR-targeting therapeutics account for approximately 36% of all marketed drugs, substantial unmet clinical needs remain [30]. Among nearly 980 recognized human disease categories, only ∼80 currently have GPCR-based targeted interventions, indicating that the vast majority of diseases—including numerous refractory and high-burden conditions—still lack effective GPCR-directed therapeutic strategies. This gap reflects three major challenges: (1) the dynamic changes in GPCR activity under pathological conditions remain poorly characterized; (2) the endogenous ligands for many GPCRs are not fully elucidated; and (3) the extraordinary complexity of downstream GPCR signaling—illustrated by the fact that three G-protein families can theoretically generate up to 1420 signaling combinations—continues to impede rational design of biased ligands aimed at minimizing adverse effects.

To address these long-standing challenges, we have established an integrated, multidisciplinary research framework that encompasses:(1) GPCR activity profiling platforms based on clinical samples [31], [32]; (2) multi-pathway, highly sensitive GPCR activity detection technologies [33], [34], [35]; (3) AI-assisted platforms for the design of high-affinity, signaling-preferential ligands; and (4) screening systems for GPCR responses to physical stimuli such as mechanical forces [36], [37], [38], [39]. Using this framework, our group has achieved a series of breakthroughs in receptor discovery and functional characterization, including: (1) identification of multiple steroid-responsive membrane receptors [40], [41], [42], [43], [44], [45]; (2) discovery of GPCRs responsive to diverse ceramide metabolites and protein-derived peptides [46], [47]; and (3) elucidation of GPCRs mediating auditory, equilibration, vestibular, olfactory, pruritic, and acid-base sensing [34], [35], [38], [48], [49], [50], [51], thereby expanding the functional landscape of GPCR biology and revealing their broader roles and mechanistic insights in GPCR mediated sensory perception. Together, these systematic efforts not only deepen our understanding of the intricate complexity of GPCR signaling but also establish technological platforms that may help overcome long-standing bottlenecks in GPCR-targeted drug discovery.