Key Concepts of Section 15.3

• G protein–coupled receptors (GPCRs) are a large and diverse family with a common structure of seven membrane-spanning α helices and an internal ligand-binding pocket that is specific for particular ligands (see Figures 15-12 and 15-13).

• GPCRs are coupled to heterotrimeric G proteins, which contain three subunits designated α, β, and γ. The G_α subunit is a GTPase switch protein that alternates between an active (“on”) state with bound GTP and inactive (“off”) state with bound GDP. The “on” form separates from the β and γ subunits and activates a membrane-bound effector. The β and γ subunits remain bound together and can also transduce signals (see Figure 15-14).

• Ligand binding causes a conformational change in certain membrane-spanning helices and intracellular loops of the GPCR, allowing it to bind to and function as a guanine nucleotide exchange factor (GEF) for its coupled G_α subunit, catalyzing dissociation of GDP and allowing GTP to bind. The resulting change in the conformation of the switch region in G_α causes it to dissociate from the G_βγ subunit and the receptor and interact with an effector protein (see Figure 15-14).

• FRET experiments demonstrate receptor-mediated dissociation of coupled G_α and G_βγ subunits in live cells (see Figure 15-15).

• The effector proteins activated (or inactivated) by heterotrimeric G proteins are either enzymes that form second messengers (e.g., adenylyl cyclase, phospholipase C) or ion channels (see Table 15-2). In each case, it is the G_α subunit that determines the function of the G protein and affords its specificity.

• GPCRs can have a range of cellular effects depending on the subtype of receptor that binds a ligand. The hormone epinephrine, for example, which mediates the fight-or-flight response, binds to multiple subtypes of GPCRs in multiple cell types, with varying physiological effects.

• Efforts to identify orphan GPCRs led to the discovery of orexins, hormones that regulate feeding behavior and sleep in both animals and humans.