12.3 GPCRs in Vision, Olfaction, and Gustation in Chapter 12 Biochemical Signaling

12.3 GPCRs in Vision, Olfaction, and Gustation

The detection of light, odors, and tastes (vision, olfaction, and gustation, respectively) in animals is accomplished by specialized sensory neurons that use signal-transduction mechanisms fundamentally similar to those that detect hormones, neurotransmitters, and growth factors. An initial sensory signal is greatly amplified by mechanisms that include gated ion channels and intracellular second messengers; the system adapts to continued stimulation by changing its sensitivity to the stimulus (desensitization); and sensory input from several receptors is integrated before the final signal goes to the brain.

The Vertebrate Eye Uses Classic GPCR Mechanisms

Visual transduction (Fig. 12-19) begins when light falls on rhodopsin, a GPCR in the disk membranes of rod cells of the vertebrate eye. (Rod cells do not detect colors; cone cells do, as we shall see in Box 12-3.) The light-absorbing pigment (chromophore) 11-cis-retinal is covalently attached to opsin, the protein component of rhodopsin, which lies near the middle of the disk membrane bilayer. When a photon is absorbed by the retinal component of rhodopsin (step ), the energy causes a photochemical change; 11-cis-retinal is converted to all-trans-retinal (see Fig. 10-20). This change in the structure of the chromophore forces conformational changes in the rhodopsin molecule, allowing it to interact with and thus activate its trimeric G protein, transducin. Rhodopsin now stimulates the exchange of bound GDP on transducin for GTP from the cytosol (Fig. 12-19, step ), and activated transducin stimulates the membrane protein cyclic GMP (cGMP) phosphodiesterase (PDE) by removing an inhibitory subunit (step ). The activated cGMP PDE degrades the second messenger $3^{'}$ $3 prime$ , $5^{'}$ $5 prime$ -cGMP to $5^{'}$ $5 prime$ -GMP, lowering [cGMP] (step ). A cGMP-dependent ${Na}^{+}$ $Na Superscript plus$ or ${Ca}^{2 +}$ $Ca Superscript 2 plus$ channel in the plasma membrane closes (step ), while a ${Na}^{+} - {Ca}^{2 +}$ $Na Superscript plus Baseline hyphen Ca Superscript 2 plus$ active antiporter continues to pump ${Ca}^{2 +}$ $Ca Superscript 2 plus$ outward across the plasma membrane (step ), making the transmembrane electrical potential more negative inside (that is, hyperpolarizing the rod cell). This electrical change passes through a series of specialized nerve cells to the visual cortex of the brain.

A figure shows the molecular consequences of photon absorption by rhodopsin with 5 steps of excitation, two steps of post-illumination recovery, and two steps of adaptation. — FIGURE 12-19 Molecular consequences of photon absorption by rhodopsin in the rod outer segment. The top half of the figure (steps to ) describes excitation; the bottom shows post-illumination steps: recovery (steps and ) and adaptation (steps and ).

FIGURE 12-19 Molecular consequences of photon absorption by rhodopsin in the rod outer segment. The top half of the figure (steps to ) describes excitation; the bottom shows post-illumination steps: recovery (steps and ) and adaptation (steps and ).

A rod is shown as a long, thin vertical rectangle with a cutout in its center left side that has three protrusions and that narrows at its base before widening into a circular piece with a circle inside, then narrowing again before expanding into a roughly triangular structure that is wider at its base with slight protrusions that extend down from the left, right, and center. The top piece of this rod is shown in close-up to the left. The upper part of the rod cell bounded by a plasma membrane is shown with a rectangular disc membrane inside that encloses an upper region labeled excitation above a bottom region labeled recovery/adaptation. Steps 1 through 5 take place in the top half and steps 6 through 9 take place in the bottom half. Step 1: Light absorption converts 11-italicized cis end italics-retinal to all-italicized trans end italics-retinal, activating rhodopsin (R h). A light red rectangular structure labeled R h has its bottom edge extending through the disk membrane. A wavy arrow points to the upper left. Within the light red structure, a six-membered ring is bonded to a 9-carbon zigzag chain that has a bend at the fifth carbon from the ring. An arrow points down to a similar structure with a straight 9-carbon zigzag chain. A green structure is immediately to the right of the light red structure. It has a small protrusion into the membrane at the bottom left connected to an oval region above that touches the light red structure with its far left side before curving back at the top, where there are two curved protrusions above the main oval portion. This entire structure is labeled T subscript Greek letter beta Greek letter gamma. This green structure overlaps another green structure to its right that has a horizontal protrusion running beneath the first green structure with a protrusion into the membrane and a right side that is an oval that angles slightly diagonally up to the right and that is labeled T subscript Greek letter alpha-G D P. Step 2: Activated rhodopsin catalyzes replacement of G D P by G T P on transducing (T), which then dissociates into T subscript Greek letter alpha-G T P and T subscript Greek letter beta Greek letter gamma. G T P to the upper right of the green structure labeled T subscript Greek letter a-G D P has a curved arrow from G T P into the structure and out to G D P. An arrow points right to a green oval with a pointed top and with a bottom that protrudes horizontally to the right and that extends a small protrusion into the membrane. It is surrounded by short radiating lines and is labeled T subscript Greek letter alpha-G T P. To its right, there is a light blue rectangle labeled P D E with curved edges with a thin vertical rectangular piece on its right side and a gray sphere on top labeled (I). Step 3: T subscript Greek letter alpha-G T P activates c G M P phosphodiesterase (P D E) by binding and removing its inhibitory subunit (I). An arrow points right to the green oval labeled T subscript Greek letter alpha-G T P, which no longer has radiating lines and which now has the gray sphere labeled (I) attached to its upper right side. To its right, P D E is shown with short radiating lines extending from all sides. Step 4: Active P D E reduces [c G M P] to below the level needed to keep cation channels open. C G M P is shown with an arrow pointing into the thin rectangular part of P D E with the radiating lines before bending upward to 5 prime-G M P above the thin rectangular part of P D E. In the cell membrane to the right, there is a thin rectangular channel with a green sphere labeled c G M P bonded to the upper left side inside of the cell. A dashed line extends from c G M P to the left of P D E surrounded by radiating lines to c G M P at the upper left of the channel. An arrow shows that N a plus and C a 2 plus move into the cell through this channel. Step 5: Cation channels close, preventing influx of N a plus and C a 2 plus; membrane is hyperpolarized. This signal passes to the brain. An arrow points down from the channel to a similar channel protein that does not have a green bound circle and that has its sides pushed together to close the channel. Step 6: Continued efflux of C a 2 plus through the N a plus- C a 2 plus exchanger reduces cytosolic [C a 2 plus]. An arrow points down from a C a 2 plus that entered through the open channel above to C a 2 plus just from the excitation upper half of the illustration and into the recovery/adaptation half, then to the left of a vertical oval in the plasma membrane and then from C a 2 plus through the oval to the area outside of the cell. Another arrow points from 4 N a plus outside of the cell through the oval to the area inside of the cell. Step 7: Reduction of [C a 2 plus] activates guanylyl cyclase (G C) and inhibits P D E; [c G M P] rises toward “dark” level, reopening cation channels and returning V subscript m to prestimulus level. A light blue oval labeled G C extends across the bottom right side of the disk membrane. It has short radiating lines extending around it and a thick crescent piece attached to its lower right. Arrow down symbol next to [C a 2 plus] has an arrow to the crescent piece. G T P has an arrow that curves part G C to c G M P, from which a dashed line points to c G M P bound to a second open channel in the lower right side of the plasma membrane. Step 8: Rhodopsin kinase (R K) phosphorylates “bleached” rhodopsin; low C a 2 plus stimulates this reaction. Arrestin (A r r) binds phosphorylated carboxyl terminus, inactivating rhodopsin. A light red vertical rectangle labeled R h extends through the membrane. Within this light red structure, a six-membered ring is bonded to a straight 9-carbon zigzag chain. A red line extending from the lower left side of the rectangle bends to run horizontally left through a light blue rectangle labeled R K. Three red circles labeled P extend down from the red line. that has a bend at the fifth carbon from the ring. An arrow points right to a similar light red rectangle with a red line extending from its upper right before bending down vertically to run through the disk membrane and into an orange square labeled A r r. The vertical red line is attached to three red circles labeled P that extend to its right within the orange square. Step 9: Slowly, arrestin dissociates, rhodopsin is dephosphorylated, and all-italicized trans end italics-retinal is replaced with 11-italicized cis end italics-retinal. Rhodopsin is ready for another phototransduction cycle. A dashed arrow points left from the light red rectangle labeled R h and an arrow curves away to show the loss of the six-membered ring bonded to a straight 9-carbon zigzag chain. Another dashed arrow shows that a six-membered ring bonded to a 9-carbon zigzag chain that has a bend at the fifth carbon from the ring is added. This produces a light red rectangle labeled R h containing six-membered ring bonded to a 9-carbon zigzag chain that has a bend at the fifth carbon.

Box 12-3 MEDICINE

Color Blindness: John Dalton’s Experiment from the Grave

Color vision involves a path of sensory transduction in specialized cells in the retina. Three types of cone cells are specialized to detect light from different regions of the spectrum, using three related photoreceptor proteins (opsins). Each cone cell expresses only one kind of opsin, but each type is closely related to rhodopsin in size, amino acid sequence, and, presumably, three-dimensional structure. The differences among the opsins, however, are great enough to place the chromophore, 11-cis-retinal, in three slightly different environments, with the result that the three photoreceptors have different absorption spectra (Fig. 1). We discriminate colors and hues by integrating the output from the three types of cone cells, each containing one of the three types of photoreceptors.

FIGURE 1 Absorption spectra of purified rhodopsin and the red, green, and blue receptors of cone cells. The receptor spectra, obtained from individual cone cells isolated from cadavers, peak at about 420, 530, and 560 nm, and the maximum absorption for rhodopsin is at about 500 nm. For reference, the visible spectrum for humans is about 380 to 750 nm. [Data from J. Nathans, Sci. Am. 260 (February):42, 1989.]

The horizontal axis is labeled wavelength (n m), ranging from below 400 to above 650, labeled in increments of 50, and the vertical axis is labeled relative absorbance, ranging from 0 to 100 and labeled in increments of 10. A bar across the horizontal axis shows color changes from left to right and begins with a dark blue color on the far left that transitions to lighter blue by 480, where it meets a green band from 480 to 545. Next is a yellow band from 545 to 585, then an orange band from 585 to 605, then a band that becomes increasingly darker red from 605 to the right end of the bar. The first curve, labeled blue pigment, is blue. It begins at (370, 60), rises to peak at (425, 100) decreases to (490, 13), then decrease more slowly to end at (540, 1). The second curve, labeled rhodopsin, is black. It begins at (400, 20), rises to peak at (500, 100) decreases to (590, 10), then decrease more slowly to end at (625, 1). The third curve, labeled green pigment, is green. It begins at (400, 20), rises to peak at (525, 100) decreases to (570, 19), then decrease more slowly to end at (660, 1). The fourth curve, labeled red pigment, is red. It begins at (475, 39), rises to peak at (565, 100) decreases to (640, 15), then decrease more slowly to end at (680, 1). All data are approximate.

Color blindness, such as the inability to distinguish red from green, is a fairly common, genetically inherited trait in humans. The various types of color blindness result from different opsin mutations. One form is due to loss of the red photoreceptor; affected individuals are ${red}^{-}$ $bold red Superscript minus$ dichromats (they see only two primary colors). Others lack the green pigment and are ${green}^{-}$ $bold green Superscript minus$ dichromats. In some cases, the red and green photoreceptors are present but have a changed amino acid sequence that causes a change in their absorption spectra, resulting in abnormal color vision. Depending on which pigment is altered, these individuals are red-anomalous trichromats or green-anomalous trichromats. Examination of the genes for the visual receptors has allowed the diagnosis of color blindness in the chemist John Dalton more than a century after his death.

Dalton (of atomic theory fame) was color-blind. He thought it probable that the vitreous humor of his eyes (the fluid that fills the eyeball behind the lens) was tinted blue, unlike the colorless fluid of normal eyes. He proposed that after his death, his eyes should be dissected and the color of the vitreous humor determined. His wish was honored. The day after Dalton’s death in July 1844, Joseph Ransome dissected his eyes and found the vitreous humor to be perfectly colorless. Ransome, like many scientists, was reluctant to throw samples away. He placed Dalton’s eyes in a jar of preservative, where they stayed for a century and a half (Fig. 2).

FIGURE 2 Dalton’s eyes.

Then, in the mid-1990s, molecular biologists in England took small samples of Dalton’s retinas and extracted DNA. Using the known gene sequences for the opsins of the red and green light receptors, they amplified the relevant sequences using PCR and determined that Dalton had the opsin gene for the red photopigment but lacked the opsin gene for the green photopigment. Dalton was a ${green}^{-}$ $green Superscript minus$ dichromat. So, 150 years after his death, the experiment Dalton started — by hypothesizing about the cause of his color blindness — was finally finished.

Several steps in the visual-transduction process result in a huge amplification of the signal. Each excited rhodopsin molecule activates at least 500 molecules of transducin, and each transducin molecule can activate a molecule of cGMP PDE. This phosphodiesterase has a remarkably high turnover number: each activated molecule hydrolyzes 4,200 molecules of cGMP per second. The binding of cGMP to cGMP-gated ion channels is cooperative, and a relatively small change in [cGMP] therefore registers as a large change in ion conductance. The result of these amplifications is exquisite sensitivity to light. Absorption of a single photon closes 1,000 or more ion channels for ${Na}^{+}$ $Na Superscript plus$ and ${Ca}^{2 +}$ $Ca Superscript 2 plus$ , hyperpolarizing the cell’s membrane by about 1 mV.

As your eyes move across this line of type, the retinal images of the first words disappear rapidly — before you see the next series of words. In that short interval, a great deal of biochemistry has taken place. Very soon after illumination of the rod or cone cells stops, the photosensory system shuts off. The α subunit of transducin ( $T_{α}$ $upper T Subscript alpha$ , with bound GTP) has GTPase activity. Within milliseconds after the decrease in light intensity, GTP is hydrolyzed and $T_{α}$ $upper T Subscript alpha$ reassociates with $T_{β γ}$ $upper T Subscript beta gamma$ . The inhibitory subunit of PDE, which had been bound to $T_{α}$ $upper T Subscript alpha$ -GTP, is released and reassociates with PDE, strongly inhibiting its activity and thus slowing cGMP breakdown.

At the same time, a second factor that helps to end the response to light is the reduction of intracellular ${[Ca}^{2 +}]$ $left-bracket Ca Superscript 2 plus Baseline right-bracket$ that results from continued ${Ca}^{2 +}$ $Ca Superscript 2 plus$ efflux through the ${Na}^{+} - {Ca}^{2 +}$ $Na Superscript plus Baseline hyphen Ca Superscript 2 plus$ exchanger (Fig. 12-19, step ). High ${[Ca}^{2 +}]$ $left-bracket Ca Superscript 2 plus Baseline right-bracket$ inhibits the enzyme that makes cGMP (guanylyl cyclase; step ), so cGMP production rises when ${[Ca}^{2 +}]$ $left-bracket Ca Superscript 2 plus Baseline right-bracket$ falls, quickly reaching its prestimulus level.

In response to prolonged illumination, rhodopsin itself undergoes changes that limit the duration of its signaling activity. The conformational change induced in rhodopsin by light absorption exposes several Thr and Ser residues in its carboxyl-terminal domain, and these residues are phosphorylated by rhodopsin kinase (step ), which is functionally and structurally homologous to the β-adrenergic kinase (βARK) that desensitizes the β-adrenergic receptor. The phosphorylated carboxyl-terminal domain of rhodopsin is bound by the protein arrestin 1, preventing further interaction between activated rhodopsin and transducin (see Fig. 12-10b). Arrestin 1 is a close homolog of arrestin 2 (βarr) of the β-adrenergic system. On a much longer time scale (step ), the all-trans-retinal bound to light-bleached rhodopsin is removed and replaced with 11-cis-retinal, making rhodopsin ready to detect another photon.

Vertebrate Olfaction and Gustation Use Mechanisms Similar to the Visual System

The sensory cells that detect odors and tastes have much in common with the visual receptor system. Binding of an odorant molecule to one of its specific GPCRs (humans have about 800 different GPCRs; rodents have about 1,200) triggers a change in receptor conformation, activating a G protein, $G_{olf}$ $upper G Subscript olf$ , analogous to transducin and to $G_{s}$ $upper G Subscript s$ of the β-adrenergic system. The activated $G_{olf}$ $upper G Subscript olf$ activates adenylyl cyclase, raising the local [cAMP]. The cAMP-gated ${Na}^{+}$ $Na Superscript plus$ and ${Ca}^{2 +}$ $Ca Superscript 2 plus$ channels of the plasma membrane open, and the influx of ${Na}^{+}$ $Na Superscript plus$ and ${Ca}^{2 +}$ $Ca Superscript 2 plus$ produces a small depolarization called the receptor potential. If a sufficient number of odorant molecules encounter receptors, the receptor potential is strong enough to cause the neuron to fire an action potential. This signal is relayed to the brain in several stages and registers as a specific smell. All these events occur within 100 to 200 ms. When the olfactory stimulus is no longer present, the transducing machinery shuts itself off in several ways. A cAMP phosphodiesterase returns [cAMP] to the prestimulus level. $G_{olf}$ $upper G Subscript olf$ hydrolyzes its bound GTP to GDP, thereby inactivating itself. Phosphorylation of the receptor by a specific kinase prevents its interaction with $G_{olf}$ $upper G Subscript olf$ , by a mechanism analogous to that used to desensitize the β-adrenergic receptor and rhodopsin. Some odorants are detected by another mechanism we have seen in other signal transductions: activation of a phospholipase and production of ${IP}_{3}$ $IP Subscript 3$ , leading to a rise in intracellular ${[Ca}^{2 +}]$ $left-bracket Ca Superscript 2 plus Baseline right-bracket$ .

The sense of taste in vertebrates reflects the activity of gustatory neurons clustered in taste buds on the surface of the tongue. In taste sensory neurons, GPCRs are coupled to the heterotrimeric G protein gustducin. When the tastant molecule binds its receptor, gustducin is activated and stimulates cAMP production by adenylyl cyclase. The resulting elevation of [cAMP] activates PKA, which phosphorylates $K^{+}$ $upper K Superscript plus$ channels in the plasma membrane, causing them to close and sending an electrical signal to the brain. Other taste buds specialize in detecting bitter, sour, salty, or umami (savory) tastants, using various combinations of second messengers and ion channels in the transduction mechanisms.

All GPCR Systems Share Universal Features

We have now looked at several types of signaling systems (hormone signaling, vision, olfaction, and gustation) in which membrane receptors are coupled to second messenger–generating enzymes through G proteins. As we have intimated, signaling mechanisms must have arisen early in evolution; genomic studies have revealed hundreds of genes encoding GPCRs in vertebrates, arthropods (Drosophila and mosquito), and the roundworm Caenorhabditis elegans. Even the common budding yeast Saccharomyces uses GPCRs and G proteins to detect the opposite mating type. Overall patterns have been conserved, and the introduction of variety has given modern organisms the ability to respond to a wide range of stimuli (Table 12-6). Of the approximately 20,000 genes in the human genome, as many as 800 encode GPCRs, including hundreds for olfactory stimuli and many orphan receptors, for which the natural ligand is not yet known.

TABLE 12-6 Some Signals That Act through GPCRs
Amines Acetylcholine (muscarinic) Dopamine Epinephrine Histamine Serotonin Peptides Angiotensin Bombesin Bradykinin Chemokine Colecystokinin (CCK) Endothelin Gonadotropin-releasing hormone Interleukin-8 Melanocortin Neuropeptide Y Neurotensin Orexin Somatostatin Tachykinin Thyrotropin-releasing hormone Vasopressin	Protein hormones Follicle-stimulating hormone Gonadotropin Lutropin-choriogonadotropic hormone Thyrotropin Prostanoids Prostacyclin Prostaglandin Thromboxane Others Cannabinoids Lysosphingolipids Melatonin Olfactory stimuli Opioids Rhodopsin

All well-studied signal-transducing systems that act through heterotrimeric G proteins share some common features that reflect their evolutionary relatedness (Fig. 12-20). 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, ${IP}_{3}$ $IP Subscript 3$ , or ${Ca}^{2 +}$ $Ca Superscript 2 plus$ ). 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 consequent electrical signal that passes to another neuron in the pathway connecting the sensory cell to the brain.

A figure shows five signaling systems that detect hormones, lights, smells, and tastes for comparison, including systems stimulated by vasopressin, epinephrine, light, an odorant, and a sweet tastant. — FIGURE 12-20 Common features of signaling systems that detect hormones, light, smells, and tastes. GPCRs provide signal specificity, and their interaction with G proteins provides signal amplification. Heterotrimeric G proteins activate or inhibit effector enzymes: adenylyl cyclase (AC) and phosphodiesterases (PDEs) that degrade cAMP or cGMP. Changes in concentration of the second messengers (cAMP, cGMP) result in alterations in enzymatic activities via phosphorylation or alterations in the permeability (P) of surface membranes to ${Ca}^{2 +}$ $Ca Superscript 2 plus$ , ${Na}^{+}$ $Na Superscript plus$ , and $K^{+}$ $upper K Superscript plus$ . The resulting depolarization or hyperpolarization of the sensory cell (the signal) passes 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. (The path of odorant detection by production of ${IP}_{3}$ $IP Subscript 3$ and increase in intracellular ${[Ca}^{2 +}]$ $left-bracket Ca Superscript 2 plus Baseline right-bracket$ , mentioned in the text, is not shown here.) VR is the vasopressin receptor; β-AR, the β-adrenergic receptor; Rh, rhodopsin; OR, olfactory receptor; SR, sweet-taste receptor.

FIGURE 12-20 Common features of signaling systems that detect hormones, light, smells, and tastes. GPCRs provide signal specificity, and their interaction with G proteins provides signal amplification. Heterotrimeric G proteins activate or inhibit effector enzymes: adenylyl cyclase (AC) and phosphodiesterases (PDEs) that degrade cAMP or cGMP. Changes in concentration of the second messengers (cAMP, cGMP) result in alterations in enzymatic activities via phosphorylation or alterations in the permeability (P) of surface membranes to ${Ca}^{2 +}$ $Ca Superscript 2 plus$ , ${Na}^{+}$ $Na Superscript plus$ , and $K^{+}$ $upper K Superscript plus$ . The resulting depolarization or hyperpolarization of the sensory cell (the signal) passes 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. (The path of odorant detection by production of ${IP}_{3}$ $IP Subscript 3$ and increase in intracellular ${[Ca}^{2 +}]$ $left-bracket Ca Superscript 2 plus Baseline right-bracket$ , mentioned in the text, is not shown here.) VR is the vasopressin receptor; β-AR, the β-adrenergic receptor; Rh, rhodopsin; OR, olfactory receptor; SR, sweet-taste receptor.

The first system has an irregular light red rectangle labeled V R with a green rounded structure labeled G subscript i attached to its lower right that has a protrusion to its upper left and two curved protrusions to its lower right, where it overlaps with a light blue rectangle labeled A C that has its top half divided vertically into two halves. An arrow points down from vasopressin to the light red rectangle labeled V R. An arrow points down from the blue rectangle labeled A C to text reading downward arrow symbol [c A M P], from which an arrow points down to a blue oval labeled P K A with a downward arrow symbol to its left. The second system has an irregular light red rectangle labeled Greek letter beta-A R with a green rounded structure labeled G subscript s attached to its lower right that has a protrusion to its upper left and two curved protrusions to its lower right, where it overlaps with a light blue rectangle labeled A C that has its top half divided vertically into two halves. An arrow points down from epinephrine to the light red rectangle labeled Greek letter beta-A R. An arrow points down from the blue rectangle labeled A C to text reading upward arrow symbol [c A M P], from which an arrow points down to a blue oval labeled P K A with an upward arrow symbol to its left. The third system has an irregular light red rectangle labeled R h with a green rounded structure labeled T attached to its lower right that has a protrusion to its upper left and two curved protrusions to its lower right, where it overlaps with a light blue rectangle labeled P D E that has a thin vertical rectangular piece on its right side. A wavy arrow points down from light to the light red rectangle labeled R h. An arrow points down from the blue rectangle labeled P D E to text reading downward arrow symbol [c G M P], from which an arrow points down to a vertical channel in a membrane with a green sphere bonded to its upper right and with text below reading, downward arrow symbol P subscript C a 2 plus, N a plus. The fourth system has an irregular light red rectangle labeled O R with a green rounded structure labeled G subscript o l f attached to its lower right that has a protrusion to its upper left and two curved protrusions to its lower right, where it overlaps with a light blue rectangle labeled A C that has its top half divided vertically into two halves. An arrow points down from odorant to the light red rectangle labeled O R. An arrow points down from the blue rectangle labeled A C to text reading upward arrow symbol [c A M P], from which an arrow points down to a vertical channel in a membrane with a piece attached to its upper left side that resembles a rectangle with a triangle attached that points downward and with text below that reads, upward arrow symbol P subscript C a 2 plus, N a plus. The fifth system has an irregular light red rectangle labeled S R with a green rounded structure labeled G subscript g u s t attached to its lower right that has a protrusion to its upper left and two curved protrusions to its lower right, where it overlaps with a light blue rectangle labeled A C that has its top half divided vertically into two halves. An arrow points down from tastant to the light red rectangle labeled S R. An arrow points down from the blue rectangle labeled A C to text reading upward arrow symbol [c A M P], from which an arrow next to a blue oval labeled P K A with an upward arrow symbol to its left points down to a vertical channel in a membrane that has its sides pinched in in the center, a bond to a red circle labeled P at the upper right, and text below reading, downward arrow symbol P subscript K plus.

All these systems self-inactivate. Bound GTP is converted to GDP by the GTPase activity of G proteins, often augmented by GTPase-activating proteins (GAPs) or regulators of G-protein signaling (RGS). In some cases, the effector enzymes that are the targets of modulation by G proteins also serve as GAPs. The desensitization mechanism involving phosphorylation of the carboxyl-terminal region followed by arrestin binding is widespread and may be universal.

SUMMARY 12.3 GPCRs in Vision, Olfaction, and Gustation

Vision, olfaction, and gustation in vertebrates employ GPCRs, which act through heterotrimeric G proteins to change the membrane potential $(V_{m})$ $left-parenthesis upper V Subscript m Baseline right-parenthesis$ of a sensory neuron.
Light activates the GPCR rhodopsin, which allosterically activates the trimeric G protein transducin. $T_{α}$ $upper T Subscript alpha$ activates a cGMP phosphodiesterase, lowering [cGMP] and closing cGMP-dependent ion channels. The resulting electrical impulse carries the signal to the brain.
In olfactory neurons, olfactory stimuli, acting through GPCRs and G proteins, trigger an increase in [cAMP] (by activating adenylyl cyclase) or ${[Ca}^{2 +}]$ $left-bracket Ca Superscript 2 plus Baseline right-bracket$ (by activating PLC). These second messengers affect ion channels and thus the $V_{m}$ $upper V Subscript m$ . Gustatory neurons have GPCRs that respond to tastants by altering levels of cAMP, which changes $V_{m}$ $upper V Subscript m$ by gating ion channels.
There is a high degree of conservation of signaling proteins and transduction mechanisms across signaling systems and across species. GPCRs with seven transmembrane helices, G proteins with intrinsic GTPase activities, cyclic nucleotides, and protein kinases are central to signaling.