Bxc

uoa

Phospholipase C

IP3, DAG (increased)

Acetylcholine receptor in endothelial cells

Gta

cGMP phosphodiesterase

cGMP (decreased)

Rhodopsin (light receptor) in rod cells

*A given Ga subclass may be associated with more than one effector protein. To date, only one major Gsa has been identified, but multiple Gqa and Gia proteins have been described. Effector proteins commonly are regulated by Ga but in some cases by Gp7 or the combined action of Ga and Gp7. IP3 = inositol 1,4,5-trisphosphate; DAG = 1,2-diacylglycerol.

sources: See L. Birnbaumer, 1992, Cell 71:1069; Z. Farfel et al., 1999, New Eng. J. Med. 340:1012; and K. Pierce et al., 2002, Nature Rev. Mol. Cell Biol. 3:639.

The signal-transducing G proteins contain three subunits designated a, p, and y. During intracellular signaling the p and y subunits remain bound together and are usually referred to as the Gpy subunit. The Ga subunit is a GTPase switch protein that alternates between an active (on) state with bound GTP and an inactive (off) state with bound GDP (see Figure 13-8). Stimulation of a coupled receptor causes activation of the G protein, which in turn modulates the activity of an associated effector protein. Although the effector protein most commonly is activated by Ga-GTP, in some cases it is inhibited. Moreover, depending on the cell and lig-and, the Gpy subunit, rather than Ga-GTP, may transduce the signal to the effector protein. In addition, the activity of several different effector proteins is controlled by different GPCR-ligand complexes. All effector proteins, however, are either membrane-bound ion channels or enzymes that catalyze formation of second messengers (e.g., cAMP, DAG, and IP3). These variations on the theme of GPCR signaling arise because multiple G proteins are encoded in eukaryotic genomes. The human genome, for example, encodes 27 different Ga, 5 Gp, and 13 Gy subunits. So far as is known, the different Gpy subunits function similarly. Table 13-1 summarizes the functions of the major classes of G proteins with different Ga subunits.

In this section, we first discuss how GPCR signals are transduced to an effector protein, a process that is similar for all receptors of this type. Then we focus on pathways in which cAMP is the second messenger, using the epinephrine-stimulated degradation of glycogen as an example.

The Ga Subunit of G Proteins Cycles Between Active and Inactive Forms

Figure 13-11 illustrates how G protein-coupled receptors transduce signals from extracellular hormones to associated effector proteins. Both the Ga and Gy subunits are linked to the membrane by covalently attached lipids. In the resting state, when no ligand is bound to the receptor, the Ga subunit is bound to GDP and complexed with Gpy. Binding of the normal hormonal ligand (e.g., epinephrine) or an ago-

► FIGURE 13-11 Operational model for ligand-induced activation of effector proteins associated with G proteincoupled receptors. The Ga and Gpy subunits of trimeric G proteins are tethered to the membrane by covalently attached lipid molecules (wiggly black lines). Following ligand binding, dissociation of the G protein, and exchange of GDP with GTP (steps 1- 3), the free GaGTP binds to and activates an effector protein (step 14). Hydrolysis of GTP terminates signaling and leads to reassembly of the trimeric form, returning the system to the resting state (step 15). Binding of another ligand molecule causes repetition of the cycle. In some pathways, the effector protein is activated by the free Gpy subunit.

Active I receptor

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