Chemogenetic Approach Using Ni(II) Complex–Agonist Conjugates Allows Selective Activation of Class A G-Protein-Coupled Receptors

[Image: see text] Investigating individual G-protein-coupled receptors (GPCRs) involved in various signaling cascades can unlock a myriad of invaluable physiological findings. One of the promising strategies for addressing the activity of each subtype of receptor is to design chemical turn-on switches on the target receptors. However, valid methods to selectively control class A GPCRs, the largest receptor family encoded in the human genome, remain limited. Here, we describe a novel approach to chemogenetically manipulate activity of engineered class A GPCRs carrying a His(4) tag, using metal complex–agonist conjugates (MACs). This manipulation is termed coordination tethering. With the assistance of coordination bonds, MACs showed 10–100-fold lower EC(50) values in the engineered receptors, compared with wild-type receptors. Such coordination tethering enabled selective activation of β(2)-adrenoceptors and muscarinic acetylcholine receptors, without loss of natural receptor responses, in living mammalian cells, including primary cultured astrocytes. Our generalized, modular chemogenetic approach should facilitate more precise control and deeper understanding of individual GPCR signaling pathways in living systems.