Rucete ✏ Lehninger Principles of Biochemistry In a Nutshell
12.3 GPCRs in Vision, Olfaction, and Gustation
This chapter explains how vertebrates detect light, odors, and tastes using specialized sensory neurons that rely on G protein–coupled receptors (GPCRs), second messengers, ion channels, signal amplification, adaptation, and neural integration. These sensory systems use molecular mechanisms closely related to hormone signaling pathways.
General Features of Sensory GPCR Systems
• Vision, olfaction, and gustation are mediated by specialized sensory neurons.
• These neurons use GPCR-based signal transduction mechanisms similar to those used for hormones, neurotransmitters, and growth factors.
• An external stimulus is converted into an intracellular biochemical signal.
• The signal is amplified through second messengers and gated ion channels.
• Systems adapt to continued stimulation by becoming less sensitive (desensitization).
• Inputs from multiple receptors are integrated before signals are sent to the brain.
The Vertebrate Eye Uses Classic GPCR Mechanisms
• Visual transduction in rod cells begins when light strikes rhodopsin.
• Rhodopsin is a GPCR located in disk membranes of rod outer segments.
• Rod cells detect light intensity but not color.
• Cone cells are responsible for color vision.
Structure of Rhodopsin
• Rhodopsin consists of opsin (protein component) plus retinal (light-absorbing chromophore).
• The retinal form present in darkness is 11-cis-retinal.
• 11-cis-retinal is covalently attached to opsin.
• The chromophore lies near the middle of the membrane bilayer.
Photon Absorption Activates Rhodopsin
• When a photon is absorbed, retinal undergoes photochemical isomerization.
• 11-cis-retinal converts to all-trans-retinal.
• This structural change forces conformational changes in opsin.
• Activated rhodopsin can now interact with its G protein.
Transducin Activation
• The trimeric G protein used in rods is transducin.
• Activated rhodopsin stimulates GDP release from transducin.
• GTP binds the α subunit.
• Transducin becomes active.
Activation of cGMP Phosphodiesterase
• Activated transducin stimulates cyclic GMP phosphodiesterase (PDE).
• It does so by removing an inhibitory subunit from PDE.
• Active PDE hydrolyzes cGMP to GMP.
• Cytosolic cGMP concentration falls.
Closure of cGMP-Gated Ion Channels
• In darkness, cGMP keeps cation channels open.
• When cGMP decreases, cGMP-gated channels close.
• Na⁺ and Ca²⁺ influx decreases.
• Meanwhile, the Na⁺/Ca²⁺ exchanger continues operating.
• Positive charge exits the cell.
• The rod cell membrane becomes more negative inside.
• This is hyperpolarization.
Transmission of Visual Signal
• Hyperpolarization changes neurotransmitter release from rod cells.
• The signal passes through retinal interneurons.
• It ultimately reaches the visual cortex of the brain.
Signal Amplification in Vision
• Visual transduction is extremely sensitive because of multiple amplification steps.
• One activated rhodopsin activates at least 500 transducin molecules.
• Each activated transducin can activate PDE.
• Each active PDE hydrolyzes about 4,200 cGMP molecules per second.
• cGMP binding to ion channels is cooperative.
• Therefore a small drop in cGMP creates a large change in ion conductance.
Single Photon Sensitivity
• Absorption of one photon can close 1,000 or more ion channels.
• This hyperpolarizes the membrane by about 1 mV.
• Rod cells are therefore extraordinarily sensitive to dim light.
Rapid Recovery after Illumination
• When light intensity falls, the response shuts off quickly.
• Transducin α has intrinsic GTPase activity.
• Bound GTP is hydrolyzed to GDP.
• Transducin becomes inactive and reassociates with βγ.
• The inhibitory subunit rebinds PDE.
• PDE activity decreases.
• cGMP breakdown slows.
Role of Calcium in Recovery
• Continued channel closure lowers intracellular Ca²⁺.
• High Ca²⁺ inhibits guanylyl cyclase.
• Therefore when Ca²⁺ falls, guanylyl cyclase becomes more active.
• cGMP is resynthesized.
• cGMP returns toward prestimulus levels.
Desensitization of Rhodopsin
• Continued illumination also reduces rhodopsin signaling.
• Activated rhodopsin exposes Thr and Ser residues in its cytoplasmic tail.
• Rhodopsin kinase phosphorylates these residues.
• Rhodopsin kinase is structurally and functionally related to β-adrenergic receptor kinase.
Arrestin in Vision
• Phosphorylated rhodopsin binds arrestin 1.
• Arrestin prevents further interaction between rhodopsin and transducin.
• This terminates receptor signaling.
Regeneration of Rhodopsin
• On a longer timescale, all-trans-retinal is removed.
• It is replaced by 11-cis-retinal.
• Rhodopsin is restored and ready to detect another photon.
Color Vision in Cone Cells
• Cone cells mediate color vision.
• Three cone cell types detect different wavelength regions.
• Each cone expresses one type of opsin.
• Cone opsins are related to rhodopsin but tuned differently.
• Differences in opsin structure alter the retinal environment and shift absorption spectra.
Human Cone Pigment Peaks
• Blue-sensitive pigment peaks near 420 nm.
• Green-sensitive pigment peaks near 530 nm.
• Red-sensitive pigment peaks near 560 nm.
• Rhodopsin peaks near 500 nm.
How Color Perception Works
• The brain compares outputs from the three cone types.
• Relative stimulation patterns create perception of hue and color.
Color Blindness
• Color blindness is often genetically inherited.
• Loss of red pigment causes red dichromacy.
• Loss of green pigment causes green dichromacy.
• Altered pigment spectra can cause anomalous trichromacy.
• Red-anomalous and green-anomalous forms also occur.
John Dalton Example
• Chemist John Dalton was color-blind.
• DNA later extracted from preserved retinal tissue showed he lacked the green opsin gene.
• This solved the cause of Dalton’s color blindness more than a century after his death.
Vertebrate Olfaction Uses Similar Mechanisms
• Odor detection occurs in olfactory sensory neurons.
• Odorant molecules bind specific olfactory GPCRs.
• Humans have about 800 GPCR genes total, many for smell.
• Rodents have about 1,200 olfactory receptors.
Golf Activation
• Odorant receptors activate the G protein Golf.
• Golf is analogous to transducin and Gs.
• Activated Golf stimulates adenylyl cyclase.
• Local cAMP concentration rises.
Ion Channel Opening in Smell
• cAMP-gated Na⁺ and Ca²⁺ channels open.
• Cation influx depolarizes the membrane.
• This graded depolarization is the receptor potential.
• If strong enough, the neuron fires an action potential.
• Signals are relayed to the brain and perceived as smell.
Speed of Olfactory Signaling
• These events occur within about 100–200 milliseconds.
Termination of Olfactory Signals
• cAMP phosphodiesterase lowers cAMP back to resting levels.
• Golf hydrolyzes GTP to GDP and inactivates itself.
• Receptor phosphorylation reduces further Golf activation.
• This mechanism resembles desensitization in β-adrenergic receptors and rhodopsin.
Alternative Olfactory Pathway
• Some odorants activate phospholipase C.
• IP₃ is produced.
• Intracellular Ca²⁺ rises.
• Ion channels are then regulated through this pathway.
Gustation Uses GPCR Signaling
• Taste sensory neurons are grouped in taste buds on the tongue.
• GPCR-mediated taste signaling uses the heterotrimeric G protein gustducin.
Taste Transduction Mechanism
• Tastant binds its receptor.
• Gustducin becomes activated.
• Adenylyl cyclase is stimulated.
• cAMP rises.
• cAMP activates PKA.
• PKA phosphorylates K⁺ channels.
• K⁺ channels close.
• Membrane potential changes.
• An electrical signal is sent to the brain.
Other Taste Modalities
• Different taste buds specialize in:
• Bitter
• Sour
• Salty
• Umami (savory)
• These use combinations of second messengers and ion channels.
Universal Features of GPCR Sensory Systems
• GPCR pathways are evolutionarily ancient and highly conserved.
• Similar systems exist in vertebrates, arthropods, worms, and yeast.
• Budding yeast use GPCRs and G proteins to detect mating type signals.
Common Structural Features
• Seven transmembrane helices.
• Cytoplasmic region that interacts with G proteins.
• Carboxyl-terminal cytoplasmic tail with reversible Ser/Thr phosphorylation sites.
• Ligand-binding or light-sensing pocket buried within membrane helices.
Common Signaling Logic
• Stimulus changes receptor conformation.
• G proteins activate or inhibit effectors such as adenylyl cyclase, PDE, or PLC.
• Second messengers such as cAMP, cGMP, IP₃, or Ca²⁺ change cellular activity.
• In endocrine systems, output is usually protein phosphorylation.
• In sensory neurons, output is a membrane potential change and nerve impulse.
Universal Self-Inactivation
• G proteins terminate themselves through GTP hydrolysis.
• GAPs or RGS proteins often accelerate this process.
• Receptor phosphorylation followed by arrestin binding is widespread and may be nearly universal.
In a Nutshell
Vision, smell, and taste rely on GPCR pathways that convert environmental stimuli into electrical signals. Rhodopsin uses transducin and cGMP in vision, olfactory receptors use Golf and cAMP in smell, and taste receptors often use gustducin with cyclic nucleotide signaling. These systems share conserved features including seven-transmembrane receptors, heterotrimeric G proteins, second messengers, amplification, adaptation, and self-termination.