Sensory Transduction in Vision, Olfaction, and Gustation:- G Protein–Coupled Serpentine Receptor Systems Share Several Features
We have now looked at four systems (hormone signaling, vision, olfaction, and gustation) in which membrane receptors are coupled to second messenger–generating enzymes through G proteins. It is clear that signaling mechanisms arose early in evolution; serpentine receptors, heterotrimeric G proteins, and adenylyl cyclase are found in virtually all eukaryotic organisms. Even the common brewer’s yeast Saccharomyces uses serpentine receptors and G proteins to detect the opposite mating type. Overall patterns have been conserved, and the in troduction of variety has given modern organisms the ability to respond to a wide range of stimuli (Table 12–8). Of the 35,000 or so genes in the human genome, as many as 1,000 encode serpentine receptors, including hundreds for olfactory stimuli and a number of “orphan receptors” for which the natural ligand is not yet known. All well-studied transducing systems that act through heterotrimeric G proteins share certain common features (Fig. 12–38). The receptors have seven transmembrane segments, a domain (generally the loop between transmembrane helices 6 and 7) that interacts with a G protein, and a carboxyl-terminal cytoplasmic domain that undergoes reversible phosphorylation on several Ser or Thr residues. The ligand-binding site (or, in the case of light reception, the light receptor) is buried deep in the membrane and includes residues from several of the transmembrane segments. Ligand binding (or light) induces a conformational change in the receptor, exposing a domain that can interact with a G protein. Heterotrimeric G proteins activate or inhibit effector enzymes (adenylyl cyclase, PDE, or PLC), which change the concentration of a second messenger (cAMP, cGMP, IP3, or Ca2+). In the hormone-detecting
systems, the final output is an activated protein kinase that regulates some cellular process by phosphorylating a protein critical to that process. In sensory neurons, the output is a change in membrane potential and a con sequent electrical signal that passes to another neuron in the pathway connecting the sensory cell to the brain.
All these systems self-inactivate. Bound GTP is con verted to GDP by the intrinsic GTPase activity of G-proteins, often augmented by GTPase-activating proteins (GAPs) or RGS proteins (regulators of G-protein signaling). In some cases, the effector enzymes that are the targets of G protein modulation also serve as GAPs.
FIGURE 12–38 Common features of signaling systems that detect hormones, light, smells, and tastes. Serpentine receptors provide sig nal specificity, and their interaction with G proteins provides signal amplification. Heterotrimeric G proteins activate effector enzymes: adenylyl cyclase (AC), phospholipase C (PLC), and phosphodiesterases (PDE) that degrade cAMP or cGMP. Changes in concentration of the second messengers (cAMP, cGMP, IP3) result in alterations of enzymatic activities by phosphorylation or alterations in the permeability (P) of surface membranes to Ca2+, Na+, and K+. The resulting depolarization or hyperpolarization of the sensory cell (the signal) is passed through relay neurons to sensory centers in the brain. In the best studied cases, desensitization includes phosphorylation of the receptor and binding of a protein (arrestin) that interrupts receptor–G protein interactions. VR is the vasopressin receptor; other receptor and G protein abbreviations are as used in earlier illustrations.
FIGURE 12–39 Toxins produced by bacteria that cause cholera and whooping cough (pertussis). These toxins are enzymes that catalyze transfer of the ADP-ribose moiety of NAD+ to an Arg residue (cholera toxin) or a Cys residue (pertussis toxin) of G proteins: Gs in the case of cholera (as shown here) and GI in whooping cough. The G proteins thus modified fail to respond to normal hormonal stimuli. The pathology of both diseases results from defective regulation of adenylyl cyclase and overproduction of cAMP.
