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. Open in a separate window 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 protein, Gi=inhibitory regulative G protein, GRK=G-protein-coupled receptor kinase, ERK=extracellular signal-regulated kinase.