A molecule meets a receptor

The nine steps

1. 01 The perfume

   On a paper strip, a drop of the house’s amber teaching accord: labdanum absolute (45 parts), vanillin (35 parts), frankincense (20 parts). As the drop evaporates, molecules of each component leave the paper. The model follows one of them: vanillin, C8H8O3.

   drawn The strip and the molecules rising from it are drawn for the idea; how many leave, and how fast, is not modeled.

   from the records · amber teaching accord

   On its record: amber teaching accord, every field there with its own source.

   from the records · vanillin

   On its record: vanillin (formula: C8H8O3), every field there with its own source.

2. 02 Into the nose

   Breathed in, the molecule reaches the olfactory epithelium high in the nose and dissolves in the mucus that covers it. Under the mucus are the fine cilia of olfactory sensory neurons, and in the membrane of each cilium sit the odorant receptors.

   drawn The membrane is drawn as two rows of lipid heads; the path the molecule takes is illustrative.

   documented · OLF-4

   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

   OLF-4 · Genovese et al. (2021). Sensory Transduction in Photoreceptors and Olfactory Sensory Neurons: Common Features and Distinct Characteristics

3. 03 A receptor

   An odorant receptor is a protein that crosses the cell membrane seven times: seven helices, joined by three loops outside the cell and three inside. It belongs to the large family of G protein-coupled receptors. Linda Buck and Richard Axel described the gene family of these receptors in the rat in 1991; the human genome carries about 400 of them.

   drawn The receptor drawn is no particular receptor. Its seven helices stand side by side, as if the bundle were unrolled; in the cell they form a ring.

   documented · OLF-5

   A common feature of these receptors is that they all possess seven transmembrane α-helices in their three-dimensional structure

   In addition to these transmembrane regions, olfactory receptors feature three extracellular loops (ECLs) and three intracellular loops (ICLs)

   discovering a large gene family comprising approximately 1,000 distinct genes, which give rise to a corresponding number of olfactory receptor types

   OLF-5 · Wang et al. (2025). Deciphering olfactory receptor binding mechanisms: a structural and dynamic perspective on olfactory receptors

   documented · OLF-4

   In both photoreceptors and OSNs, the detection of stimuli is mediated by G protein-coupled receptors.

   OLF-4 · Genovese et al. (2021). Sensory Transduction in Photoreceptors and Olfactory Sensory Neurons: Common Features and Distinct Characteristics

   documented · TXT-BUCK-AXEL-1991

   TXT-BUCK-AXEL-1991 · Linda Buck and Richard Axel

   Linda Buck and Richard Axel. A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 65 (1991) 175–187. Publisher (Elsevier BV), DOI 10.1016/0092-8674(91)90418-X (checked 2026-10-08).

   documented · OLF-6

   This task is accomplished by the combinatorial activation of approximately 400 odorant G protein-coupled receptors encoded in the human genome.

   OLF-6 · Billesbølle CB, de March CA, van der Velden WJC, Ma N, Tewari J, del Torrent CL, Li L, Faust B, Vaidehi N, Matsunami…

4. 04 Binding

   The molecule settles into a pocket among the helices. It is held by weak contacts, not a lasting chemical bond, and for a matter of milliseconds before it lets go. In the structure of one human receptor, OR51E2, its odorant (propionate) sits in a small enclosed pocket.

   drawn No receptor for vanillin is drawn here: the pocket, the fit and the angle are illustrative. Most odorant receptors have no known odorant yet; a 2025 review’s table of receptors with reported odorants lists vanillin for five of them (OR1L3, OR2G2, OR2M4, OR2T10 and OR2T34), all from one 2015 study.

   documented · OLF-4

   The binding of the ligand to the receptor protein is noncovalent and rapidly reversible.

   the dwell time of the odorant ligand on the OR appears to be very short and on a millisecond timescale

   OLF-4 · Genovese et al. (2021). Sensory Transduction in Photoreceptors and Olfactory Sensory Neurons: Common Features and Distinct Characteristics

   documented · OLF-6

   Propionate is bound within an occluded pocket in OR51E2 and makes specific contacts critical to receptor activation.

   OLF-6 · Billesbølle CB, de March CA, van der Velden WJC, Ma N, Tewari J, del Torrent CL, Li L, Faust B, Vaidehi N, Matsunami…

   documented · OLF-5

   the current landscape reveals that more than 80% of olfactory receptors remain enigmatic orphan receptors while their ligands shrouded in mystery

   Deorphanized olfactory receptor (ORs) with corresponding ligand.

   Rows of the table, as the filed text gives them (receptor | odorants, their names run together | reference):

   • OR1L3 | vanillinα-damascone | Gonzalez-Kristeller et al. (2015)
   • OR2G2 | maltyl isobutyratecinnamaldehydevanillinα-damascone | Gonzalez-Kristeller et al. (2015)
   • OR2M4 | fructonecinnamaldehydevanillinnerolidolα-damascone estragolecresyl methyl ether | Gonzalez-Kristeller et al. (2015)
   • OR2T10 | maltyl isobutyrateterpinyl acetate; cinnamaldehydevanillinα-damascone | Gonzalez-Kristeller et al. (2015)
   • OR2T34 | fructone; cinnamaldehydefloralozonevanillin; α-damasconejasmonylestragole | Gonzalez-Kristeller et al. (2015)

   OLF-5 · Wang et al. (2025). Deciphering olfactory receptor binding mechanisms: a structural and dynamic perspective on olfactory receptors

5. 05 The receptor changes shape

   Bound, the receptor changes shape. On the inside of the membrane it activates its G protein, Golf, which splits in two: Gαolf, carrying GTP in place of GDP, and the pair Gβγolf. In the OR51E2 structure, the change that switches the receptor on runs through its third outer loop.

   drawn One helix tilts outward; the drawing exaggerates the movement so it can be seen.

   documented · OLF-4

   the ligand-activated OR proteins bind to the G protein Golf, causing its dissociation into active Gαolf and olfactory β- and γ-subunit, Gβγolf

   the exchange of GDP for GTP on Gαolf and its activation

   OLF-4 · Genovese et al. (2021). Sensory Transduction in Photoreceptors and Olfactory Sensory Neurons: Common Features and Distinct Characteristics

   documented · OLF-6

   Molecular dynamics simulations demonstrate that propionate-induced conformational changes in extracellular loop 3 activate OR51E2.

   OLF-6 · Billesbølle CB, de March CA, van der Velden WJC, Ma N, Tewari J, del Torrent CL, Li L, Faust B, Vaidehi N, Matsunami…

6. 06 A messenger, cAMP

   Gαolf binds to an enzyme in the membrane, adenylyl cyclase 3, and switches it on. The enzyme makes cyclic AMP (cAMP), a messenger inside the cilium: one activated enzyme makes most likely hundreds of molecules. The receptor step itself adds no gain; the cAMP is where the signal grows.

   drawn Nine cAMP molecules stand for hundreds.

   documented · OLF-4

   Curiously, the activation of Golf by the OR molecule does not result in amplification.

   Gαolf is part of the Gαs 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

   The activation of AC3 by Golf results in the synthesis of most likely hundreds of cAMP molecules

   OLF-4 · Genovese et al. (2021). Sensory Transduction in Photoreceptors and Olfactory Sensory Neurons: Common Features and Distinct Characteristics

7. 07 Channels open

   cAMP opens the cyclic-nucleotide-gated (CNG) channels in the membrane, and sodium and calcium ions flow into the cilium. The calcium opens a second channel, Anoctamin 2, and chloride ions flow out. Both currents raise the voltage across the neuron’s membrane.

   drawn Filled dots are sodium and calcium ions, open circles chloride; their number is illustrative.

   documented · OLF-4

   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 which further depolarizes the OSNs

   OLF-4 · Genovese et al. (2021). Sensory Transduction in Photoreceptors and Olfactory Sensory Neurons: Common Features and Distinct Characteristics

8. 08 A nerve signal

   The rise in voltage makes the neuron fire action potentials, brief electrical spikes that travel along its axon to the olfactory bulb of the brain. One molecule is not enough: a neuron needs around thirty binding events before it fires reliably.

   drawn The voltage trace is drawn for the idea, not taken from a recording.

   documented · OLF-4

   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

   cannot be activated by a single odorant molecule but instead require around 30 odorant binding events to begin firing action potentials reliably

   OLF-4 · Genovese et al. (2021). Sensory Transduction in Photoreceptors and Olfactory Sensory Neurons: Common Features and Distinct Characteristics

9. 09 Back to the perfume

   One odorant is recognised by several receptors, one receptor by several odorants, and different odorants by different combinations: the brain reads the pattern across many receptors, not a single one. Vanillin is one of the three components of this accord; labdanum absolute and frankincense are natural materials, each a mixture of molecules of its own, read by combinations of their own.

   drawn The row of lit receptors is an illustrative pattern, not a measurement for vanillin or for any receptor.

   documented · OLF-7

   We found that one OR recognizes multiple odorants and that one odorant is recognized by multiple ORs, but that different odorants are recognized by different combinations of ORs.

   Thus, the olfactory system uses a combinatorial receptor coding scheme to encode odor identities.

   OLF-7 · Malnic et al. (1999). Combinatorial receptor codes for odors

   documented · OLF-6

   This task is accomplished by the combinatorial activation of approximately 400 odorant G protein-coupled receptors encoded in the human genome.

   OLF-6 · Billesbølle CB, de March CA, van der Velden WJC, Ma N, Tewari J, del Torrent CL, Li L, Faust B, Vaidehi N, Matsunami…

   from the records · labdanum absolute

   On its record: labdanum absolute, every field there with its own source.

   from the records · frankincense

   On its record: frankincense, every field there with its own source.