The Structural Basis of G‐Protein‐Coupled Receptor Signaling (Nobel Lecture)

Complex organisms require a sophisticated communication network to maintain homeostasis. Cells from different parts of our bodies communicate with each other using chemical messengers in the form of hormones and neurotransmitters. Cells process information encoded in these chemical messages using G-protein-coupled receptors (GPCRs) located in the plasma membrane. GPCRs also mediate communication with the outside world. The senses of sight, smell and taste are mediated by GPCRs. GPCRs are nature's most versatile chemical sensors. There are over 800 GPCRs in the human genome and they respond to a broad spectrum of chemical entities ranging from photons, protons and calcium ions, small organic molecules (including odorants and neurotransmitters), to peptides and glycoproteins. The classical role of a GPCR is to detect the presence of an extracellular agonist, transmit the information across the plasma membrane, and activate a cytoplasmic heterotrimeric G protein, leading to modulation of downstream effector proteins. Taking the human β2 adrenergic receptor (β2AR) as an example, binding of adrenaline leads to activation of Gαs, stimulation of adenylyl cyclase, cAMP accumulation, PKA activation, and phosphorylation of proteins involved in cell metabolism (Figure 1). However, a wealth of research has now demonstrated that many GPCRs have more complex signaling repertoires. For example, the β2AR couples to both Gαs and Gαi in cardiac myocytes,[1] and can also signal through MAP kinase pathways in a G-protein-independent manner via arrestin.[2, 3] Similarly, the process of GPCR desensitization involves multiple pathways, including receptor phosphorylation events, arrestin-mediated internalization into endosomes, receptor recycling, and lysosomal degradation. These activities are further complicated by the possibility of GPCR oligomerization,[4] and the localization of receptors to specific membrane compartments having different complements of signaling proteins and different lipid bilayer compositions. Such multifaceted functional behavior has been observed for many different GPCRs. Figure 1 The complex signaling and regulatory behavior of the β2AR. The inset illustrates the concept of ligand efficacy. PKA=protein kinase A, PKC=protein kinase C, PDE=phosphodiesterase, cAMP=cyclic adenosin monophosphate, Gs=stimulative regulative G ... How does this complexity of functional behavior reconcile with the biochemical and biophysical properties of GPCRs? The effect of a ligand on the structure and biophysical properties of a receptor, and thereby the biological response, is known as the ligand efficacy. Natural and synthetic ligands can be grouped into different efficacy classes (Figure 1 inset): 1) full agonists are capable of maximal receptor stimulation; 2) partial agonists are unable to proffer full activity even at saturating concentrations; 3) neutral antagonists have no effect on signaling activity, but can prevent other ligands from binding to the receptor; 4) inverse agonists reduce the level of basal or constitutive activity below that of the unliganded receptor. For GPCRs capable of coupling to multiple signaling systems, specific ligands can have differential relative efficacies towards the different pathways. In the extreme case, even opposite activities towards different signaling pathways are observed: for the β2AR, agonists toward the arrestin/MAP kinase pathway are also inverse agonists for the classical Gαs/cAMP/PKA pathway.[2,5] Given the central role played by GPCRs in nearly all physiologic processes, they represent the largest group of targets for drug discovery for a broad spectrum of diseases. A better understanding of the structural basis for the complex signaling behavior of GPCRs should lead to more efficient and economical approaches to drug discovery.