28.17: Signal Transduction - Vision and Olfaction

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Learning Goals (ChatGPT o3-mini)

1. Describe Specialized Cellular Structures:

   • Explain the unique architecture of photoreceptors (rods and cones) and olfactory sensory neurons (OSNs), including the role of specialized cilia and membrane structures in signal detection.
   • Compare the structural differences between rod outer segments (stacked disk membranes) and cone outer segments (plasma membrane invaginations), and relate these differences to their functional roles in light detection.

2. Understand Signal Detection Mechanisms:

   • Outline how visual pigments in photoreceptors, with covalently bound chromophores, convert light into a molecular signal.
   • Describe how odorant receptors in OSNs detect volatile molecules through noncovalent, reversible interactions, and how these receptors initiate the olfactory transduction cascade.

3. Analyze Transduction Cascades:

   • Detail the molecular steps of the phototransduction cascade, including the activation of rhodopsin, the role of transducin, and the subsequent changes in cGMP levels that lead to hyperpolarization.
   • Compare and contrast the olfactory transduction cascade, highlighting the roles of odorant receptors, Golf, adenylyl cyclase 3 (AC3), cAMP production, and the opening of cyclic nucleotide-gated channels leading to depolarization.

4. Evaluate Signal Amplification Strategies:

   • Explain the mechanisms that amplify the initial sensory signal in photoreceptors, such as the multiple activation of transducin by a single photoactivated rhodopsin and the cooperative gating of CNG channels.
   • Describe how OSNs achieve signal amplification via a secondary Ca²⁺-activated Cl⁻ current following cAMP-mediated activation, and discuss the advantages of using Cl⁻ over Na⁺ in the olfactory cilia.

5. Examine Inactivation and Adaptation Processes:

   • Illustrate how photoreceptors inactivate their response through phosphorylation, arrestin binding, and GTP hydrolysis, ensuring rapid reset for subsequent stimuli.
   • Discuss the feedback mechanisms mediated by Ca²⁺ in both photoreceptors and OSNs that lead to adaptation, including the roles of GCAPs, recoverin, and Na⁺/Ca²⁺ exchangers in maintaining sensitivity over a wide dynamic range.

6. Integrate Electrophysiological Techniques:

   • Describe how loose-patch (suction pipette) recording techniques are used to measure stimulus-induced electrical responses in photoreceptors and OSNs.
   • Interpret electrophysiological data showing graded potentials in photoreceptors versus action potentials in OSNs, and relate these differences to their respective sensory functions.

7. Relate Molecular Mechanisms to Sensory Function and Disease:

   • Connect the structural and functional properties of phototransduction and olfactory transduction to their roles in high-sensitivity signal detection and discrimination.
   • Analyze how mutations or disruptions in transduction components (e.g., visual pigment misfolding, CNG channel dysfunction, or OR mutations) can lead to sensory disorders, such as retinitis pigmentosa or anosmia, and discuss potential therapeutic strategies.

By achieving these learning goals, students will develop a comprehensive understanding of how specialized sensory neurons convert external stimuli into electrical signals, how these signals are amplified and terminated, and how these processes are critical for proper sensory function and adaptation.

This chapter section is taken in its entirety from Genovese et al Front. Cell. Neurosci., 08 October 2021 | https://doi.org/10.3389/fncel.2021.761416. Creative Commons Attribution License (CC BY)

Sensory Transduction in Photoreceptors and Olfactory Sensory Neurons

Photoreceptors and olfactory sensory neurons (OSNs) have highly specialized structures that enable them to capture their respective stimuli of light and odorant ligands. Both photoreceptors and OSNs have evolved highly specific abilities to detect and discriminate light wavelengths or odors. They use intricate transduction mechanisms to convert sensory stimuli into electrical signals. Their transduction cascades can greatly amplify the signal and enhance the signal-to-noise, enabling these cells to detect and distinguish minute stimuli within very noisy background conditions. Such transduction mechanisms provide for modulation at multiple steps to adapt the sensory neurons to different background stimulation and optimize the capture of useful information about the surrounding world.

In this review, we summarize some of the key structural and functional features of vertebrate rod and cone photoreceptors and OSNs, as well as the molecular mechanisms underlying their function. While describing the features of both cell types, we emphasize the similarities and differences between photoreceptors and OSNs and the unique features of each cell type that make them perfectly suited to perform their function.

Signal Detection in Photoreceptors and Olfactory Sensory Neurons’ Specialized Cilia

Vertebrate rod, cone photoreceptors, and OSNs are ciliary neurons, as shown in Figure \(\PageIndex{1}\).  They have specialized cilia, where the sensory stimulus's initial detection occurs to activate a sensory transduction cascade. Rods and cones have a single cilium that has evolved to accommodate a stack of ~1,000 membrane disks where the visual pigment is expressed at a very high 3–5 mM concentration.  In the case of rods, the disks are enveloped by the plasma membrane, whereas in cones the disks are formed by invaginations of the plasma membrane. As light enters the eye and reaches the retina, it travels along the length of the rod and cone outer segments. The orientation of the elongated outer segments along the light path and the high density of visual pigment in their disks result in ~50% probability that a visual pigment molecule absorbs an incident photon. In the case of OSNs (right panel), odorant ligands are detected in the ~20 cilia protruding from each dendritic knob which are immersed in the mucus layer covering the olfactory epithelium. The olfactory cilia, which are motile in amphibians but not in rodents, are only about 0.1–0.2 μm thin but can reach up to 100 μm in length depending on the species. While this greatly increases the surface membrane area available to incorporate olfactory receptor (OR) proteins to detect odorants, it also greatly reduces the ciliary volume with potentially detrimental effects (see below).

Figure \(\PageIndex{1}\): Photoreceptors and olfactory sensory neurons (OSNs).

(A) Simplified schematic representation of a rod and a cone in the retina. Photoreceptors are polarized neurons with a specialized morphology optimized to detect light stimuli. The outer segments of both rods and cones are modified sensory cilia, containing membrane disks organized in a stack. In the case of rods, the outer segment has a slim rod-like structure in which the plasma membrane encloses the disks. The outer segment of the cones has a stocky conical-shaped structure, in which invaginations of the plasma membrane constitute the disks. The outer segment does not contain any proteins of the cell translation machinery, which are mostly localized in the inner segment, including the endoplasmic reticulum, Golgi, and mitochondria. Outer and inner segments are connected by the connecting cilium. In contrast, distal to the inner segment is the cell body containing the nucleus, followed by the axon and synaptic termini that extend into the outer plexiform layer where they synapse with the second-order neurons. When the light enters the eye, after reaching the retina, it travels along the length of the rod and cone inner segment until finally reaching the outer segments.

(B) Simplified schematic of an OSN in the olfactory epithelium. OSNs are ciliated bipolar neurons, their apical dendrites extend to the surface of the epithelium terminating with a spherical structure called a dendritic knob, from which the sensory cilia enter the mucus layer. The ciliary membrane contains the olfactory receptors (ORs) necessary to detect different odorants. Distal from the knob is the cell body of the OSN with its nucleus, followed by a long axon that projects to the olfactory bulb, where it synapses with the second-order neurons. Images created with BioRender.com.

Electrophysiological Approaches to Record Light- and Odorant-Induced Responses

The similar morphological structure of rods, cones, and OSNs, with a ciliary part able to detect the respective stimuli and an adjacent cell body, allows similar electrophysiological approaches to recording stimulus-induced responses in these cell types. The cell body of a photoreceptor or an OSN can be sucked into the tip of a recording pipette by using a loose-patch (or suction pipette) recording configuration. This leaves the outer segment of photoreceptors or the olfactory cilia exposed and accessible to bath solution changes, e.g., the application of pharmacological agents or odorants, in the case of OSNs. Suction pipette recordings can be performed from isolated sensory neurons, as shown in Figure \(\PageIndex{2}\) (A, B, and D show a salamander rod, salamander cone, and salamander OSN) but also from dissected retina tissue, as in the case of the outer segment of a mouse rod drawn in the recording electrode from a piece of the retina (C). This recording configuration measures the transduction current entering the photoreceptor outer segment or olfactory cilia, and leaving via the cell body.

Figure \(\PageIndex{2}\):  Figures modified from Reisert and Matthews (2001), Kefalov et al. (2010), and Kefalov (2012) with permission.

A fundamental difference between photoreceptors’ and OSNs’ responses to stimuli lies in their polarity. In the absence of light, rods and cones are kept depolarized by a standing inward current of approximately 20–40 pA for amphibian cones and rods, and 7–15 pA for mouse photoreceptors. This depolarizing current is gradually suppressed upon light stimulation until, for sufficiently high light intensities, it is reduced to zero, as shown in  Figure \(\PageIndex{3}\) (A, B, mouse rod, and cone responses, respectively), leading to photoreceptor hyperpolarization. Similar to rods, but unlike cones, the OSNs show comparatively little spontaneous activity without stimuli. Different OSNs show varying levels of spontaneous basal activity determined by the constitutive activity of their ORs.

Figure \(\PageIndex{3}\): Modified from Kefalov et al. (2010), Sakurai et al. (2011), Deng et al. (2013), and Dibattista and Reisert (2016) with permission.

In the presence of odorants, OSNs generate an inward receptor current that leads to depolarization and the generation of action potentials. This receptor current is odorant concentration-dependent and increases progressively with increasing stimulation until it eventually saturates at high odorant concentrations. Responses recorded from OSNs expressing different olfactory receptors can generate fairly different response amplitudes when stimulated with their respective agonists (Panel D, E): responses recorded from mouse OSNs that express the mOR-EG or the M71 olfactory receptor, which are activated by the ligands eugenol and acetophenone, respectively.

The hyperpolarization and signals carried by graded potentials in photoreceptors vs. depolarization and signals carried by action potentials in OSNs represent another fundamental difference between these two types of sensory neurons. These topics and the differences in synaptic structure and transmission between photoreceptors and OSNs go beyond the focus of this review.

Sensitivity of Photoreceptors and Olfactory Sensory Neurons

Due to their unique structure, photoreceptors and, to a lesser extent, OSNs have achieved exquisite sensitivity that optimizes the detection of stimuli within the respective sensory organs. In addition, both sensory receptors use a transduction cascade to amplify the signal (see below). As a result, rod photoreceptors can reliably detect single photons, enabling humans to perceive light with as few as six photons detected by adjacent rods. This renders rods perfectly suited for dim light vision, with a dynamic range spanning lights from a dark, cloudy night to sunrise. Cones are ~100-fold less sensitive than rods, making them suited for daytime light conditions. Figure \(\PageIndex{3C}\) compares the intensity-response function of mouse rods and cones, demonstrating the much lower sensitivity of cones compared to rods.

Most OSNs respond to odor concentrations in the low micromolar range, but they can also reach exquisite sensitivity and are capable of detecting odors at the nanomolar concentration range. Picomolar sensitivity is reached by a subset of OSNs that express receptors specialized in detecting amines, the trace-amine-associated receptors. Compared to rods, OSNs do not reach such high sensitivity. A single odorant molecule cannot activate them; instead, it requires around 30 odorant binding events to begin firing action potentials reliably. The detection of odorants in the olfactory epithelium can be further enhanced by expressing a wider number of different OR genes, more than 350 in humans and 1,000 in mice, with overlapping response profiles to odorants. A larger number of OSNs, particularly in species relying heavily on their sense of smell, may further enhance the detection of odorants. For instance, the human olfactory epithelium covers ~3–4 cm² and contains approximately 5–6 million OSNs, while in the case of dogs, the area of the olfactory epithelium is 18–150 cm² and contains 150–300 million OSNs.

Detection of Stimuli

In both photoreceptors and OSNs, the detection of stimuli is mediated by G protein-coupled receptors. In photoreceptors, this function is achieved by rod and cone visual pigments, which consist of a protein, opsin, covalently attached to the visual chromophore, typically 11-cis-retinal. The chromophore is a reverse agonist, keeping the receptor molecule in the inactive ground state. Absorption of a photon by 11-cis-retinal triggers its conformational change to all-trans-retinal, which, in turn, results in the rearrangement of the opsin transmembrane helices and switch of the visual pigment molecule into its active state.

We discussed bacterial rhodopsin in an earlier section. We present it here again to show and note its similarity to animal light-sensing proteins.

Review: Retinal, Opsin and Light Transduction in Bacteria

Microbial rhodopsins are phototransducing proteins with a conjugated chromophore retinal, covalently attached to the protein opsin through a Schiff base (imine) linkage. The holoprotein (opsin with the attached retinal) is called rhodopsin. Retinal is derived from beta-carotene. The structures of animal and microbial retinals are shown below.

 Structures of animal and microbial retinals

When light of the correct wavelength is absorbed, an electron in a pi molecular orbital in retinal is promoted to a pi antibonding molecular orbital, breaking a 2-electron pi bond in the structure at a certain site in the isoprenoid chain, allowing rotation around the now single bond. After the electrons return to the ground state, the final result is photoisomerization of the trans 13-14 and cis 11-12 bonds in microbial and animal retinal, respectively, to their respective cis 13-14 and trans 11-12 configuration. This conformational change in the bound retinal induces a conformational change in the protein opsin, leading to signaling.

The figure below shows an interactive iCn3D model of one monomeric of bacteria rhodopsin (1C3W) containing retinal attached through a Schiff base to Lys 216.

Bacterial rhodopsin (1C3W). (Copyright; author via source). Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...9HzvfdFvb9kcc6

The covalently attached retinal is shown in gray spacefill. Opsin is a membrane protein that spans the membrane with seven helices. Hence, it is very similar to a GPCR.

The activated visual pigment then binds to a G protein, transducin, activating it. The transducin activation triggers the transduction cascade that ultimately generates the cellular response. Eventually, the all-trans-retinal chromophore is released from opsin after the covalent Schiff base between them is hydrolyzed, leaving behind chromophore-free opsin. Notably, without a chromophore, opsin has residual activity, and in sufficient quantities can produce steady activation of the photoreceptors, similar to steady background light, thus modulating the sensitivity of photoreceptors. This process is known as bleaching adaptation, indicating the production of free opsin after the photoactivation of the visual pigment and dissociation of the visual chromophore.

Unlike in photoreceptors, where the ligand, a light-sensitive reverse agonist, is covalently attached to opsin, in olfaction, the ligands are dissolved in the mucus covering the surface of the olfactory epithelium and come into direct contact with the OR proteins expressed in the OSN ciliary membrane. This results in the activation of the receptor protein that, in turn, is transduced downstream to a G protein to trigger a transduction cascade resulting in the cellular response. The binding of the ligand to the receptor protein is noncovalent and rapidly reversible. ORs, like other G protein-coupled receptors, display antagonism, inverse, and partial agonism, leading to suppressed responses to their agonists, a reduction in basal activity without stimulation, or suppression of the maximal response.

Recent Updates: 7/25/24

Detection of Odorants in Insects - The Effects of DEET

DEET (N,N-diethyl-meta-toluamide) is the active ingredient in many mosquito and insect repellents.  It's been widely used for a long time, but its biochemistry is still unclear.  It inhibits olfactory signaling pathways in insects.  These pathways involved olfactory receptors (OR), odorant-binding proteins (OBPs), and other mostly downstream proteins.  Studies have progressed furthest on the small soluble OBPs found in mosquito lymph, which consists of three classes: pheromone-binding proteins, general OBPs, and antennal binding proteins X. The OBPs likely bind and transport generally low-solubility odorants as part of the initial steps in signal transmission. Likely, the odorant:OBP complex binds to an odorant receptor.  An individual OBP also likely binds to different odorants with similar structural topology and chemical properties, as the number of recognized odorants greatly exceeds the number of OBPs.

The classic OBP contains six alpha-helices and three disulfide bonds. The figure below shows an interactive iCn3D model of the Odorant Binding Protein 1 from Anopheles gambiae (AgamOBP1) with bound DEET (N,N-Diethyl-meta-toluamide) and PEG 216 (3N7H).

Odorant Binding Protein 1 from Anopheles gambiae (AgamOBP1) with DEET (N,N-Diethyl-meta-toluamide) and PEG 216 (3N7H). (Copyright; author via source). Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...wWGmkkJeoQvC38

The crystal structure is a dimer (colored magenta and blue), which is likely the biological unit since the protein concentration is high in insect lymph (which could drive dimerization).  OBP1 has two ligands bound in each subunit, polyethylene glycol (PEU, a crystallization agent) and DEET (DE3).  The iCn3D structure above shows the amino acids in both dimers that are 5 Angstrom (Å) from the bound PEGs.   The PEG binds in a hydrophobic, L-shaped tunnel (green surface coloring indicates a hydrophobic pocket). The interactions are predominantly nonpolar with one hydrogen bond to a water molecule. DEET binds with a reported K_d of 31 μM near the entrance in the short segment of the L-shaped tunnel. Since DEET and PEG bind to different parts of the tunnel, the tunnel can likely accommodate other odorants of similar topology and hydrophobicity.  Little conformational change occurs on the binding of DEET compared to the unliganded protein.  The protein has the Uniprot ID Q8WRX3, but nothing about its interaction partners is described. 

In contrast, insect odorant receptors (OR) are tetrameric, ligand-gated ion channels.  On binding of the odorant, the channel is gated open.  The OR often binds coreceptors that facilitate channel restructure and opening.  It is unclear from the literature if the odorant binding protein 1 is a coreceptor for an odorant receptor or delivers odorants (such as DEET) to the receptor.  The animations below show the closed and open form of the Ap OR5-Orco heterocomplex from the pea aphid Acyrthosiphon pisum.  A conformational change occurs when the odorant geranyl acetate is added (not shown).  The active structure contains the OR5 receptor and the Orco coreceptor.

Figure:  Ap OR5-Orco heterocomplex from the pea aphid Acyrthosiphon pisum morphing from the closed to the open channel on binding of the odorant geranyl acetate (8Z9Z to 8Z9A).  Image made using Pymol.

Insect odorant receptors have an intracellular N-terminus, an extracellular C-terminus, and seven transmembrane helices. Hence, they are very similar to GPCRs but with a flipped orientation, so they can't couple to intracellular G-proteins. Rather, they are ligand-gated ion channels. They bind proteins named Orco, which act as co-receptors.  

The olfactory receptor MhOR5 from the jumping bristletail Machilis hrabei is a homotetrameric odorant-gated ion channel that binds a broad range of odorants.   Several are shown below, along with the non-odorant molecule glucose.

The activity of several odorants including eugenol (an oily substance found in clove, nutmeg, cinnamon, basil and bay leaf), geosmin (a fungal metabolite that confers the smell in the air after a fresh rain), DEET, and a negative control, glucose, is shown in the figure below.

Figure:  Left, activity of MhOR5 evoked by a panel of 54 small molecule ligands. Right, dose–response curves of MhOR5 to selected ligands. del Mármol, J., Yedlin, M.A. & Ruta, V. The structural basis of odorant recognition in insect olfactory receptors. Nature 597, 126–131 (2021). https://doi.org/10.1038/s41586-021-03794-8.  Creative Commons Attribution 4.0 International License.  http://creativecommons.org/licenses/by/4.0/.

Notice that Eugenol binds with an apparent Kd of around 2 uM (antilog of -5.7, the log [Ligand] at half-maximal binding (as measured by changes in fluorescence), while geosmin and DEET have a Kd closer to 100 uM.

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Discrimination Between Stimuli

The spectral sensitivity of individual rod and cone photoreceptors is dictated by the absorption properties of their visual pigments. Typically, each photoreceptor type expresses only one type of opsin; in the case of the human retina, rods express rod opsin, whereas cones express long wavelength (LW, red), middle wavelength (MW, green), or short wavelength (SW, blue) opsin. When bound to the chromophore, the amino acid structure of each opsin determines the optical properties of the resulting visual pigment and the spectral sensitivity of the photoreceptors expressing it. As a result, species existing in environments with characteristic light distribution, such as deep-sea fish, have visual pigments that have evolved to optimize their spectral sensitivity. A second factor controlling the optical properties of the visual pigment is the structure of the visual chromophore. Most species, including mice and humans, use 11-cis-retinal, a derivative of Vitamin A, also known as A1. However, some amphibians and fish also use 3,4-dehydro 11-cis retinal, also known as A2. This chromophore has an extra conjugated double bond in its structure, which shifts the absorption spectrum of A2 visual pigments to longer wavelengths than the A1 visual pigment embedded in the same opsin molecule. Some aquatic and amphibian species use the A1/A2 chromophores to shift their spectral sensitivity from murky waters dominated by longer wavelengths of light to seawater and air, dominated by shorter wavelengths of light. One notable example includes the toad, where the retina is populated by A1 visual pigment in its ventral section, receiving light from above the surface of the water, and by A2 visual pigment in its dorsal section, receiving light from below the surface of the water. A shift in the chromophore can also occur during the lifetime of the animal as its environment changes, such as the A2 to A1 shift in salamanders as they metamorphose from the larval (aquatic) to the adult (terrestrial) stage, or the A2 to A1 shift in Atlantic salmon during migration from sea to freshwater.

Similar to photoreceptors, the ligand specificity of the OSNs is also dictated by the expression of OR genes in their cilia. As photoreceptors, each OSN generally expresses only one receptor gene, so the OR's structure determines its ligand specificity expressed in that particular cell. However, photoreceptors typically use no more than five opsin genes to cover the visible spectrum. In contrast, OSNs can use hundreds, in the case of humans, to thousands or more, for rodents and dogs, OR genes to cover the odor space. The same OR can be activated by multiple odorants with different sensitivities.  A given odorant can activate different ORs with different half-maximal concentrations. This generates a complex mosaic of ORs and odorant response pairs. Figure \(\PageIndex{3F}\) compares the dose responses of OSNs expressing either the mOR-EG or the M71 OR to eugenol and acetophenone, respectively. In this case, mOR-EG OSNs display higher sensitivity to their agonist than M71 OSNs. However, this does not preclude the possibility that the M71 OR is more sensitive to another ligand resulting in a more left-shifted dose-response relation than the one seen with acetophenone. Conversely, the dose-response relation of M71 OSNs to benzaldehyde is approximately 10-fold right-shifted compared to acetophenone.

Determining the ligand specificity of ORs is an ongoing endeavor. Due to the large number and diversity of OR genes and the nearly endless number of odorant molecules, understanding the overall mechanisms that control their ligand binding affinity and specificity remains challenging. Receptor modeling approaches to understanding and predicting OR–odorant molecule interactions can provide valuable insights, but they are somewhat hampered by the lack of a crystal structure of any vertebrate OR. The rhodopsin structure is often used as a guide and homology model to predict the structure of ORs.

Sensory Transduction Activation

In both photoreceptors and OSNs, the detection of stimuli by their respective G protein-coupled receptors is converted into electrical signals via the activation of a G protein-coupled to a second messenger transduction cascade. The two pathways, though distinct, share an amazing level of similarity, as shown in Figure \(\PageIndex{4}\). Thus, the second messenger in both cases is a cyclic nucleotide, cGMP in photoreceptors and cAMP in OSNs. As a result, the activation of both transduction cascades results in a rapid shift in the equilibrium between synthesis and hydrolysis of the respective cyclic nucleotide, which is then sensed by the cyclic nucleotide-gated (CNG) transduction channels in the plasma membrane of the photoreceptor outer segment or olfactory cilium.

Figure \(\PageIndex{4}\): Activation of the transduction cascade in rod photoreceptors and OSNs.

(A) Schematic representation of phototransduction cascade in rods. Abbreviations: rhodopsin (Rh), Tα, β, and γ subunits of the retinal G protein, transducin (T), guanosine-5′-triphosphate (GTP), guanosine-5′-diphosphate (GDP), phosphodiesterase (PDE), guanosine monophosphate (GMP), and cyclic guanosine monophosphate (cGMP), and cyclic nucleotide-gated (CNG) channel.

(B) Schematic representation of the olfactory transduction cascade in OSNs. Abbreviations: Olfactory receptor (OR), guanosine-5′-triphosphate (GTP), guanosine-5′-diphosphate (GDP), Gα_olf, β, and γ, subunits of the olfactory G protein; adenylyl cyclase 3 (AC3), adenosine-5′-triphosphate (ATP), cyclic adenosine monophosphate (cAMP), cyclic nucleotide-gated (CNG) channel; Ca²⁺-activated Cl⁻ channel anoctamin 2 (ANO2). Images created with BioRender.com.

In the case of photoreceptors, the photoactivated visual pigment binds to and activates the trimeric G protein transducin (T) (Panel A), causing the exchange of GDP for GTP on its α-subunit, which is part of the Gα_t protein family. Following the subsequent dissociation of the α-subunit (Tα) from its β/γ complex (Tβγ), Tα then binds to the cGMP phosphodiesterase (PDE) complex, relieving the inhibition of its catalytic α- and β-subunits by its inhibitory γ-subunits. All these transduction proteins are embedded in or tethered to the disc membranes inside rods or contained in cones' cell membranes. As a result of their activation, the hydrolysis of free cGMP in the outer segment is upregulated, causing its rapid decline, and partial or complete closure of the cGMP-gated channels expressed in the rod and cone cell membranes. The closure of the CNG channels leads to the reduction of the inward transduction current, followed by the hyperpolarization of the cells, and a reduction of neurotransmitter release to second-order neurons within the retina. Inversely, in the absence of light, the opening of CNG channels and the resulting inward transduction current is sustained by the continuous cGMP production by guanylyl cyclase (GC).

Similarly, in OSNs (Panel B), the ligand-activated OR proteins bind to the G protein G_olf, causing its dissociation into active Gα_olf and olfactory β- and γ-subunits, Gβγ_olf. In contrast to transducin, however, Gα_olf is part of the Gα_s protein family and binds to adenylyl cyclase 3 (AC3), activating it. As a result, the synthesis of cAMP in the olfactory cilia is upregulated, causing its rapid increase and the opening of cAMP-gated channels.

While photoreceptors and OSNs use CNG transduction channels, their respective channels have different subunit compositions. Rods and cones express heterotetramers consisting of the main A1 and A3 and the modulatory B1a and B3 subunits in 3:1 and 2:2 stoichiometric, respectively. The olfactory CNG channel is a heterotetramer consisting of two units of the main A2 subunits and one each of the modulatory A4 and B1b subunits. Interestingly, the rod and the olfactory CNG channels express different splice variants of the same B1 subunit. In OSNs, the initial inward Na⁺ and Ca²⁺ current generated by the opening of the CNG channel raises ciliary Ca²⁺ and opens a secondary ion channel, the Ca²⁺-activated Cl⁻ channel Anoctamin 2. A high intraciliary Cl− maintained by the Na⁺/K⁺/2Cl⁻ cotransporter 1 ensures a Cl⁻ efflux further depolarizes the OSNs. This depolarization triggers the generation of action potentials, which further propagate along the axons, inducing glutamate release at synapses with the second-order neurons in the olfactory bulb. In photoreceptors, the transduction cascade upon stimulation does not ultimately generate action potentials in the receptor cell, but only a graded receptor potential that directly causes a change in neurotransmitter release.

Amplification

As for any other sensory modality, proper amplification of the signal is required to detect small stimuli, and the resulting high sensory sensitivity is critical for the survival and propagation of the species. Nature has reached the highest physically possible sensitivity in the case of rod photoreceptors that can produce a detectable electrical response to the absorption of a single photon. This impressive feat is achieved by employing a transduction cascade that allows tremendous signal amplification. During the ~50 ms active lifetime, a single photoactivated rhodopsin molecule activates ~20 transducins, producing an immediate 20-fold amplification. The following activation of PDE by transducin does not directly produce amplification, as each transducin has to bind to a PDE molecule to activate it. However, once activated, each PDE enzyme can hydrolyze thousands of cGMP molecules. Lastly, as the binding of cGMP to the CNG transduction channels is cooperative, a slight change in cGMP levels can reduce the number of cGMP molecules bound to the channel from 3 to 2. This results in channel closure and a sharp reduction in the transduction current, further enhancing the detection of photostimulation. Despite the similarities in the transduction cascades of rods and cones, the amplification in cone photoreceptors is substantially lower due to fine-tuning at several of the phototransduction steps. Interestingly, even though rod and cone visual pigments activate transducin with similar efficiencies, the lower thermal stability of the cone visual pigment results in higher intrinsic activity in cones compared to rods in darkness, effectively desensitizing the cones and shifting their function towards brighter daytime light conditions as shown in Figure \(\PageIndex{3C}\).

Curiously, the activation of G_olf by the OR molecule does not result in amplification. Indeed, the dwell time of the odorant ligand on the OR appears to be very short and on a millisecond timescale. As a consequence, on average, this results in the activation of less than one G protein per activated receptor. As such, in contrast to phototransduction, where the lifetime of the activated rhodopsin greatly influences the response size and kinetics, in OSNs the response depends more prominently on the coupling efficacy of downstream transduction components. At the same time, the odorant presence keeps the OR activated. OSNs employ a secondary amplification step on top of the cAMP transduction cascade to compensate for the lack of initial amplification at the G protein level. The activation of AC3 by Golf results in the synthesis of most likely hundreds of cAMP molecules, the opening of the CNG channels, which is followed by a unique secondary amplification based on excitatory Ca²⁺-activated Cl⁻ channels in the cilia, as shown in Figure \(\PageIndex{4B}\). The Cl⁻ current carries up to 80% of the overall transduction current. Physiological experiments with pharmacological and genetic modulation of the Cl⁻ conductance indicate that the Cl⁻ channels set the length of the action potential train generated in response to odorant stimulation and to promote recognition of novel odorants.

A puzzling aspect of the secondary amplification step is why Cl⁻ is the charge-carrying ion, not Na⁺. This could be achieved easily by increasing the expression level and/or the ion permeation and conductance of the olfactory CNG channel. Recent theoretical work hinted at two main advantages of Cl⁻, instead of Na⁺, as the charge carrier. As the external environment of cilia is the nasal mucus, currents will depend on the ion concentration in the mucus, which can be unstable. A current that depends on the intracellular ion concentration, as for Cl⁻ but not for Na⁺, is much less dependent on the mucosal ion concentration. For instance, this could become an issue in the case of a cold with a runny nose or during swimming, when the mucus becomes diluted. The second advantage results from the “compromise” to increase the ciliary surface area, which has the expense of having a very small ciliary volume, in the femtoliter range. Even small ionic currents can lead to large changes in ion concentration and osmotic pressures in such small volumes. If the main charge carrier were Na⁺, this would lead to a large increase (tens of mM). This would cause a large increase in osmotic pressure and prevent Ca²⁺ clearance via the olfactory Na⁺/Ca²⁺, K⁺ exchanger (see below) with greatly deleterious effects.

In contrast, high intracellular Cl⁻ is maintained throughout the OSN so that diffusion from the cell soma rapidly reverses its local depletion in the cilia upon ligand activation. Both these issues do not exist for photoreceptors as they are embedded in the interstitial fluid of the eye. Photoreceptors are sufficiently large, and their transduction currents are sufficiently small that ion concentration changes due to changes in transduction currents are relatively small. Nevertheless, rod photoreceptors undergo osmotically driven length changes upon light activation, an effect that is mitigated by the translocation of G protein subunits into the cytosol.

Receptor and G Protein Inactivation

Timely and effective transduction inactivation is critical for allowing sensory neurons to continue to detect stimuli with high temporal resolution. Equally important is to extract behaviorally relevant information from the presented stimuli. All active transduction components must be turned off in both photoreceptors and OSNs. The cyclic nucleotide level within the cells must be restored to the resting level before the sensory cell can be reset to the inactive state and become ready for subsequent activation, as shown in Figure \(\PageIndex{5}\). In the case of photoreceptors, the identity of the step determining the overall kinetics of the photoresponse inactivation was the subject of intense research and debate over several decades. As the visual chromophore ligand is covalently attached to opsin, inactivation of the visual pigment could be extremely slow. Indeed, if left on its own, the active state of rhodopsin decays with a time constant of ~50 s. Its inactivation in photoreceptors is a two-step process, involving phosphorylation of the rhodopsin C-terminus by rhodopsin kinase (GRK1), which partially quenches its activity, followed by the binding of arrestin1, which completely inactivates the visual pigment (Panel A). Though the decay of the active state of cone pigment is significantly faster at ~2 s, this is still clearly too slow to enable the timely termination and reset of phototransduction. Thus, in both rods and cones, the visual pigments are inactivated by phosphorylation by rhodopsin kinase and the subsequent arrestin binding long before they decay spontaneously. The effective time constant of rod visual pigment inactivation is ~50 ms. The slowest step in the inactivation of rod phototransduction turned out to be the hydrolysis of GTP, which shuts off Tα, a reaction driven by the transducin GTPase activity and enhanced by a GTPase-activating protein (a GAP) complex consisting of Gβ5 and the membrane-anchoring protein R9AP. Inactivation of transducin results in its release from PDE, allowing the two PDE γ inhibitory subunits to resume their inhibition on this enzyme's two catalytic subunits (α and β). The kinetics of this reaction determines the overall kinetics of response inactivation in rod photoreceptors. In contrast, work from amphibian cones suggests that in cones, the photoresponse duration is Ca²⁺-dependent and involves the quenching of the cone visual pigment.

Figure \(\PageIndex{5}\): Termination of transduction cascade in rod photoreceptors and OSNs.

(A) Schematic representation of the termination of phototransduction in rods. Abbreviations: Phosphorylated light-activated rhodopsin (Rh*-P), arrestin (ARR), G protein-coupled receptor kinase 1 (GRK1), Tα, β, and γ subunits of the retinal G protein, transducin (T), guanosine-5′-triphosphate (GTP), guanosine-5′-diphosphate (GDP), phosphodiesterase (PDE), guanosine monophosphate (GMP) and cyclic guanosine monophosphate (cGMP), and cyclic nucleotide-gated (CNG) channel, guanylate cyclase (GC), guanylate cyclase-activating protein (GCAP), cyclic nucleotide-gated (CNG) channels, K⁺ dependent Na⁺/Ca²⁺ exchanger 1, 2 and 4 (NCKX1, NCKX2, NCKX4).

(B) Schematic representation of the termination of the olfactory transduction cascade. Abbreviations: Olfactory receptor (OR), arrestin (ARR), G protein-coupled receptor kinase 3 (GRK3) Gα_olf, β, and γ, subunits of the olfactory G protein, guanosine-5′-triphosphate (GTP), guanosine-5′-diphosphate (GDP), adenylyl cyclase 3 (AC3), activated phosphodiesterase 1C (PDE1C), cyclic adenosine monophosphate (cAMP), adenosine monophosphate (AMP), Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), cyclic nucleotide-gated channel (CNG); Ca²⁺-activated Cl⁻channel anoctamin 2 (ANO2), K⁺-dependent Na⁺/Ca²⁺ exchanger 4 (NCKX4). Images created with BioRender.com.

In OSNs, the inactivation by phosphorylation and arrestin are potentially not needed for the timely shutoff of the olfactory transduction cascade, due to the extremely short lifetime of the active ligand-bound receptor molecule. Early biochemical experiments suggested that OR phosphorylation does control cAMP kinetics. Still, it seems to play little, if any, role in controlling odorant-response kinetics for one particular OR, mOR-EG. It remains to be established whether this applies to all ORs or whether a subset of ORs is subject to phosphorylation and inactivation. β-arrestin interacts with ORs, mediating internalization during prolonged stimulation and altering adaptation to repetitive odor stimuli. Experiments on isolated human and rat OSNs suggested a role for protein kinases A (PKA) and C (PKC) in the termination of the olfactory response. Ca²⁺ imaging showed that the inhibition of PKA and PKC increases intracellular Ca²⁺ responses in the presence of odorant mixtures and blocks their termination after odorant stimulation ceases. While the inhibition of both PKA and PKC modulated the odor-induced intracellular Ca²⁺ increase in the human OSNs, only PKC and not PKA affected the Ca²⁺ response to odorants in rat OSNs, suggesting differences among species in the termination of the olfactory response.

The control of the lifetime of the olfactory G protein seems to be more complex and less well-understood compared to phototransduction. Ric-8B (resistant to inhibitors of cholinesterase-8B) has been identified as a GTP exchange factor (GEF) expressed in OSNs, which facilitates the exchange of GDP for GTP on Gα_olf and its activation. Unusually, Ric-8B not only interacts with the G protein α-subunit but also with γ13, the olfactory γ-subunit. In a heterologous system, Ric-8B co-expression with olfactory transduction components can greatly increase cAMP production, suggesting it could modulate olfactory transduction. A knockout mouse for Ric-8B displays impaired olfactory behavior, and, surprisingly, greatly reduced odorant responses. Ric-8B is localized primarily in the cell body and the dendritic knob of OSNs. Ric-8B knockout OSNs are devoid of Gα_olf, suggesting that this gene is needed for the stable expression of Gα_olf, and excludes addressing its potential role as a GEF in the odorant response. The Ric-8B knockout mice also display higher OSN cell death. Regulators of G protein signaling (RGS) are GAPs that modulate the lifetime of an activated G protein as described above. RGS2, instead of functioning as a GAP, directly inhibits AC3 to control the size of the odorant response. However, inconsistent and contradictory data on RGS2 and RGS3 expression and their roles in OSNs suggest that more research is needed.

Adaptation

Adaptation plays a critical role in the capacity of our sensory neurons to remain able to detect stimuli above the background in a complex and rapidly changing environment. For instance, in constant light conditions, the dynamic range for rods and cones is only 100-fold, spanning a range from threshold stimulation to saturation as shown in Figure \(\PageIndex{3C}\). However, due to light adaptation, photoreceptors can shift their functional range over a wide range of light conditions, ranging from cloudy night to sunrise for rods, and starry night to bright sunny day for cones. Thus, using the adaptation of individual photoreceptors, the visual system can remain responsive to stimuli over a wide range of light conditions. In contrast, the ability of OSNs to adapt is somewhat limited even at modest levels of background odorant. Nevertheless, increasing concentrations of the same odorant can recruit less sensitive ORs, and therefore less sensitive OSNs, preserving its perception at higher concentrations and ensuring that it reports the presence of that odorant to the brain.

In both types of sensory neurons, adaptation is mediated by a change in Ca²⁺ upon stimulation. This change is sensed by several Ca²⁺-binding proteins that trigger a negative feedback on the vision and olfaction transduction cascades by modulating several of their steps. In the outer segments of rods and cones and olfactory cilia, Ca²⁺ levels are controlled by the balance of influx via the CNG channels, whose current is carried in part by Ca²⁺, and efflux via Na⁺/Ca²⁺, K⁺ exchangers (NCKXs) that use the electrochemical gradient for Na⁺ and K⁺ to extrude Ca²⁺ as shown in Figure \(\PageIndex{5}\). In rods (Panel A), this task is accomplished by rod-specific NCKX1, whereas cones employ two separate exchangers, NCKX2 and NCKX4. At rest, both in darkness and in steady-state light, the influx of Ca²⁺ is matched with its extrusion and, as a result, the level of free Ca²⁺ in the outer segments is maintained constant. Upon photostimulation, the transduction cascade is activated, resulting in the depletion of cGMP, closure of CNG channels, and reduction in the influx of Ca²⁺ into the outer segments. However, Ca²⁺ extrusion by the Na⁺/Ca²⁺ and the K⁺ exchangers continues for a while and, as a result, the level of Ca²⁺ in the outer segments declines. Direct Ca²⁺ measurements in amphibian photoreceptors indicate a dynamic range from 670 to 30 nM in rods and 400–5 nM in cones, in darkness and bright light, respectively.

The light-driven decline in Ca²⁺ causes its release from several Ca²⁺-binding proteins. The dominant Ca²⁺-dependent feedback mechanism in both rods and cones controls the synthesis of cGMP by membrane-bound GC via a pair of GC-activating proteins (GCAPs)—GCAP1 and GCAP2. When Ca²⁺ in the outer segments is high, Ca²⁺-bound GCAPs bind to and partially inhibit the activity of GC. Upon photoactivation and the decline in Ca²⁺, GCAPs become Ca²⁺-free and release from GC, resulting in the upregulation of cGMP synthesis, which restores the dark current after photostimulation and modulates the activation of the transduction cascade in the presence of background light. Another mechanism by which Ca²⁺ modulates phototransduction involves the Ca²⁺-binding protein recoverin. As a GCAP, recoverin is a member of the EF-hand protein family. When bound to Ca²⁺ in darkness, it inhibits rhodopsin kinase, thus slowing down the inactivation of the visual pigment. When the photoreceptors are activated and Ca²⁺ declines, it is released from the recovery.  This then dissociates from rhodopsin kinase and relieves its inhibition. This enhances the phosphorylation of visual pigments and accelerates their inactivation, effectively reducing the background light's activation of the transduction cascade. Finally, direct modulation of the CNG channels has also been suggested. However, in the case of rods, such modulation appears to play a marginal, at best, role and is not mediated by the Ca²⁺-binding protein calmodulin. In zebrafish cones, the modulation of the CNG channels appears to play a more substantial role and is mediated by the Ca²⁺-binding protein CNG-modulin. It is still unclear whether the mammalian homolog of CNG modulin, EML1, plays a similar role in mammalian cones.

Adaptation in OSNs is less well understood than phototransduction. Early data, mostly of biochemical nature or obtained from heterologously-expressed proteins of interest, suggested three main molecular targets for adaptation. All three of them are mediated by the Ca²⁺ influx during the odorant response: Ca²⁺/calmodulin-mediated desensitization of the olfactory CNG channel to close the channel even in the presence of high cAMP; phosphorylation via CaM-kinase 2 of AC3 to reduce the rate of cAMP production; and Ca²⁺-mediated upregulation of phosphodiesterase 1C, which is expressed in olfactory cilia, and is assumed to degrade cAMP to AMP to terminate the response. Follow-up experiments using recordings from OSNs all indicate that none of these mechanisms play as prominently or as originally thought in transduction. A mouse with a mutation in the CNGB1b channel subunit that entirely prevents desensitization by Ca²⁺, surprisingly displays normal olfactory adaptation but instead shows a delayed response termination, suggesting that Ca²⁺/calmodulin-mediated desensitization of the CNG channel speeds up response termination. A mouse model with a mutation in AC3 that prevents phosphorylation does not show a discernible phenotype of the olfactory response. However, it might be possible that other, unknown phosphorylation sites in AC3 might be important. Finally, a knockout mouse for PCE1C has no deficits in response termination but shows much-reduced response amplitudes for unclear reasons. This begs the obvious question of what the role of PDE1C might be and what might occur to cAMP generated during the odorant response. For the latter, an interesting option is that cAMP diffuses out of the cilia into the cell body to reduce ciliary cAMP, allowing OSNs to recover from stimulation. One reasonably understood aspect is NCKX4, the Ca²⁺ exchanger in OSNs that is required to lower intraciliary Ca²⁺ during and after odorant stimulation, allowing the transduction cascade to recover from adaptation.

Diseases

Disorders affecting photoreceptors are among the leading causes of blindness in the human population. One of the prevalent visual disorders, called retinitis pigmentosa, is a complex disease caused by a wide range of mutations in photoreceptors. Many of these mutations affect the rod's visual pigment's expression, structure, and function. Because of the very high expression of opsin in the outer segments of rods, this protein plays not only a functional role. Still, it is also critical for properly forming the outer segment itself. As a result, mutations affecting the expression, folding, or targeting of opsin to the rod outer segments cause gradual degeneration of the rods. Other genes implicated in rod dysfunction and degeneration include those for phosphodiesterase (e.g., rd1, rd10; the CNG channels A and B subunits (channelopathies;), GC, and GCAPs. Another diverse set of visual disorders is caused by abnormal chromophore production or supply to photoreceptors, limiting the ability to detect light and leading to degeneration. Notably, the visual system's efficiency in producing chromophore seems to decline with age, which may result in poor rod function in dim light even in normally aging adults. It is also an early indicator of age-related macular degeneration. This devastating blinding disorder affects the function of cones in the central retina, which are responsible for acute vision and color discrimination. Interestingly, rods and cones seem to coexist synergistically in the retina, and diseases caused by rod-specific mutations that result in rod degeneration eventually lead to the loss of cones and central vision. Thus, considerable efforts are currently focused on developing methods for preserving rods even when they are not functional to protect daytime cone-driven vision. Because the eye is a relatively accessible organ, novel therapeutic approaches for vision protection and restoration have led the field, with successful gene and stem cell therapy examples in experimental and clinical trial phases.

Compared to vision, in olfactory transduction, very few mutations in transduction components are known that lead to deleterious effects. Several aspects might account for this. Mutations causing a partial reduction of olfaction might go unnoticed in the human population, as very little systematic olfactory testing is done. OSNs regenerate throughout life and only have a lifespan of a few weeks. Hence, as seen in photoreceptors, any slow degeneration might not manifest in that time window. In a screen of families with congenital anosmia, no potentially causative mutations were found in three main transduction proteins (G_αolf, CNGA2, and AC3), with these genes also being under purifying selection. An interesting exception is patients suffering from retinitis pigmentosa, which is caused by mutations in the gene encoding the CNGB1 subunit expressed in rods and OSNs. Those patients, identified because of their visual function decline, were found hyposmic or anosmic when tested for their olfactory ability. If congenital anosmia is considered a relatively rare and little-understood condition, specific anosmias are better known and frequently detected, manifesting in the inability to detect certain odorants. This is the olfactory equivalent of color blindness caused by known OR mutations.

Arguably, the most common causes of smell loss are events that lead to the destruction of the olfactory epithelium and/or the olfactory nerves connecting it to the central nervous system (CNS). These events include head or face trauma, inhalation of toxic chemicals, or viral infection (such as SARS-CoV-2), and neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. In the former, the origin of the smell disorder can be traced to the periphery, the olfactory epithelium. In the case of neurodegenerative diseases, it has been thought that olfactory dysfunction originates centrally in the CNS. Still, it is becoming clearer now that peripheral olfaction can be affected in these cases as well, although the respective mechanisms have not been fully elucidated.

Summary

This chapter explores the molecular and cellular mechanisms by which specialized sensory neurons convert external stimuli into electrical signals. Focusing on vertebrate photoreceptors (rods and cones) and olfactory sensory neurons (OSNs), the chapter highlights how distinct structures and signaling cascades are optimized for the detection of light and odorants, respectively, while also discussing common themes such as signal amplification, inactivation, and adaptation.

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Specialized Cellular Architecture

• Photoreceptors:
  Rods and cones are highly polarized, ciliary neurons that use their modified outer segments for light detection. In rods, the outer segment contains a stack of approximately 1,000 membrane disks densely packed with visual pigments, where each disk is enclosed by the plasma membrane. Cones, on the other hand, feature disk structures formed by invaginations of the plasma membrane. This organization, coupled with the precise alignment of the outer segments to incoming light, maximizes photon absorption.

• Olfactory Sensory Neurons:
  OSNs extend multiple (approximately 20) slender, elongated cilia from their dendritic knobs into the mucus layer covering the olfactory epithelium. These cilia provide a large surface area for the expression of olfactory receptors (ORs), which are responsible for detecting a vast array of odorant molecules.

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Signal Detection and Transduction Mechanisms

• Detection by G Protein-Coupled Receptors (GPCRs):
  Both photoreceptors and OSNs rely on GPCRs to detect stimuli. In photoreceptors, visual pigments consist of an opsin protein covalently bound to a chromophore (typically 11‑cis‑retinal). Absorption of light triggers isomerization of the chromophore to all‑trans‑retinal, inducing conformational changes in opsin that activate the transduction cascade.
  In OSNs, odorant molecules bind noncovalently to olfactory receptors located on the ciliary membrane. Despite similarities to other GPCRs, these receptors are part of a complex network that discriminates among a wide variety of odorants.

• Transduction Cascades:
  In photoreceptors, activated visual pigment (e.g., photoactivated rhodopsin) engages a specific heterotrimeric G protein (transducin). This leads to the exchange of GDP for GTP on the Gα subunit, which then dissociates and activates cGMP phosphodiesterase (PDE). The resultant decrease in cGMP levels causes the closure of cyclic nucleotide-gated (CNG) channels, reducing the inward current and hyperpolarizing the cell.
  In contrast, odorant binding in OSNs activates the olfactory G protein (Golf). The activated Gαolf stimulates adenylyl cyclase 3 (AC3), leading to an increase in cAMP levels. Elevated cAMP opens CNG channels, allowing an influx of cations (primarily Na⁺ and Ca²⁺) that depolarize the neuron and trigger action potentials. Notably, OSNs employ an additional amplification step via Ca²⁺-activated Cl⁻ channels, which enhance the depolarization.

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Signal Amplification and Sensitivity

• Photoreceptor Amplification:
  Phototransduction in rods is extraordinarily sensitive—capable of detecting single photons. This sensitivity is achieved by a cascade in which one activated rhodopsin molecule activates multiple transducin molecules, and each activated PDE hydrolyzes thousands of cGMP molecules. Furthermore, the cooperative nature of cGMP binding to CNG channels ensures that even small changes in cGMP levels produce significant changes in channel conductance and membrane potential.

• Olfactory Sensitivity:
  Although OSNs do not achieve the single-molecule sensitivity of rods, they are finely tuned to detect odorants even at nanomolar concentrations. The initial G protein activation by odorant-bound receptors may be modest; however, the robust secondary amplification via cAMP synthesis and Ca²⁺-activated Cl⁻ channel activation ensures that even minimal odorant binding leads to a significant electrical response. In addition, the large number of OR genes and the diverse array of OSNs contribute to the broad detection and discrimination of odorant molecules.

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Inactivation and Adaptation Mechanisms

• Termination of the Signal:
  For both photoreceptors and OSNs, timely inactivation of the signaling cascade is crucial to prevent continuous activation and to allow rapid recovery for subsequent stimuli. In photoreceptors, active visual pigments are rapidly inactivated through phosphorylation by rhodopsin kinase followed by arrestin binding. GTP hydrolysis on transducin, accelerated by a GTPase-activating protein complex, further ensures rapid signal termination.
  In OSNs, although receptor phosphorylation and arrestin-mediated internalization may play a role, the transient binding of odorants typically results in a short-lived active state. Additionally, proteins such as Ric-8B and regulators of G protein signaling (RGS) modulate the duration of the odorant response, although the precise mechanisms remain less well defined than in photoreceptors.

• Adaptation Processes:
  Adaptation allows sensory neurons to adjust their sensitivity based on the prevailing background levels of stimulation. In photoreceptors, adaptation is largely mediated by changes in intracellular Ca²⁺ levels. When light reduces cGMP and closes CNG channels, the subsequent decline in Ca²⁺ triggers feedback mechanisms via GCAPs and recoverin that restore cGMP synthesis and accelerate pigment inactivation. OSNs also utilize Ca²⁺-dependent feedback mechanisms, such as Ca²⁺/calmodulin-mediated modulation of CNG channel sensitivity and regulation of cAMP levels, to fine-tune their responses and maintain dynamic sensitivity in fluctuating odor environments.

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Implications for Sensory Function and Disease

• Functional Relevance:
  The precise control of signal amplification, inactivation, and adaptation in photoreceptors enables the visual system to operate over an enormous range of light intensities—from starlight to bright daylight. Similarly, the complex transduction mechanisms in OSNs allow for the discrimination of an immense variety of odorants despite the inherently low stimulus concentrations.

• Pathological Considerations:
  Mutations or dysfunctions in key components of these signaling pathways can lead to sensory disorders. For example, mutations in visual pigment or CNG channel components are associated with retinitis pigmentosa and other forms of degenerative blindness. In the olfactory system, while genetic defects are less commonly identified, disruptions due to environmental damage or neurodegenerative diseases can result in anosmia (loss of smell) or hyposmia (reduced sense of smell).

In summary, this chapter integrates the structural, biochemical, and electrophysiological aspects of sensory transduction in photoreceptors and OSNs. It highlights how specialized cellular architectures and finely tuned signaling cascades enable these neurons to convert light and odorant stimuli into robust electrical signals, and it discusses the mechanisms that ensure both high sensitivity and rapid adaptation. Understanding these processes not only provides insights into the fundamental principles of sensory biology but also informs the development of therapeutic approaches for sensory disorders.