Olfactory receptor
Encyclopedia
Olfactory receptors expressed in the cell membrane
s of olfactory receptor neuron
s are responsible for the detection of odor
molecules. Activated olfactory receptors are the initial player in a signal transduction
cascade which ultimately produces a nerve impulse which is transmitted to the brain. These receptors are members of the class A rhodopsin-like
family of G protein-coupled receptor
s (GPCRs). The olfactory receptors form a multigene family consisting of over 900 genes in humans and 1500 genes in mice.
s, the olfactory receptors are located in the cilia of the olfactory sensory neurons. In insect
s, olfactory receptors are located on the antennae
and other chemosensory organs. Sperm
cells also express odor receptors, which are thought to be involved in chemotaxis
to find the egg cell.
, olfactory receptors display affinity for a range of odor
molecules, and conversely a single odorant molecule may bind to a number of olfactory receptors with varying affinities. Once the odorant has bound to the odor receptor, the receptor undergoes structural changes and it binds and activates the olfactory-type G protein
on the inside of the olfactory receptor neuron. The G protein
(Golf
and/or Gs
) in turn activates the lyase - adenylate cyclase
- which converts ATP
into cyclic AMP (cAMP). The cAMP opens cyclic nucleotide-gated ion channel
s which allow calcium
and sodium
ion
s to enter into the cell, depolarizing the olfactory receptor neuron and beginning an action potential
which carries the information to the brain
.
The primary sequences of thousands of olfactory receptors (ORs) are known from the genomes of more than a dozen organisms: they are seven-helix transmembrane proteins, but there are (as of July 2011) no known structures of any OR. There is a highly conserved sequence in roughly three quarters of all ORs that is a tripodal metal ion binding site , and Suslick
has proposed that the ORs are in fact metalloproteins (mostly likely with zinc, copper and possibly manganese ions) that serve as a Lewis Acid site for binding of many odorant molecules.
In a recent but highly controversial interpretation, it has also been speculated that olfactory receptors might really sense various vibrational energy-levels of a molecule rather than structural motifs via quantum coherence mechanisms. As evidence it has been shown that flies can differentiate between two odor molecules which only differ in hydrogen isotope (which will drastically change vibrational energy levels of the molecule).
It should be noted, however, that deuteration changes the heats of adsorption and the boiling and freezing points of molecules (boiling points: 100.0C for H20 vs. 101.42 for D20; melting points: 0.0C for H20, 3.82C for D2O), pKa (i.e., dissociation constant: 9.71x10^-15 for H20 vs. 1.95x10^-15 for D2O, cf. Heavy water
) and the strength of hydrogen bonding. Such isotope effects
are exceedingly common, and so it is well known that deuterium substitution will indeed change the binding constants of molecules to protein receptors.
which represents approximately 3% of the genes in the genome. However not all of these potential odor receptor genes are expressed and are functional. According to an analysis of data derived from the human genome project
, humans have approximately 400 functional gene
s coding for olfactory receptors and the remaining 600 candidates are pseudogene
s.
The reason for the large number of different odor receptors is to provide a system for discriminating between as many different odors as possible. Even so, each odor receptor does not detect a single odor. Rather each individual odor receptor is broadly tuned to be activated by a number of similar odorant structures. Analogous to the immune system
, the diversity that exists within the olfactory receptor family allows molecules that have never been encountered before to be characterized. However, unlike the immune system, which generates diversity through in-situ recombination
, every single olfactory receptor is translated from a specific gene; hence the large portion of the genome devoted to encoding OR genes. Furthermore most odors activate more than one type of odor receptor. Since the number of combinations and permutations
of olfactory receptors is almost limitless, the olfactory receptor system is capable of detecting and distinguishing between a practically infinite number of odorant molecules.
system has been devised for the olfactory receptor family and is the basis for the official Human Genome Project (HUGO
) symbols for the gene
s that encode these receptors. The names of individual olfactory receptor family members are in the format "ORnXm" where:
For example is the first isoform of subfamily A of olfactory receptor family 1.
Members belonging to the same subfamily of olfactory receptors (>60% sequence identity) are likely to recognize structurally similar odorant molecules.
Two major classes of olfactory receptors have been identified in humans:
s or gene conversion
s. Tandem duplications are evidenced by the fact that many olfactory receptor genes belonging to the same phylogenetic clade
are located in the same gene cluster
. Birth-and-death evolution also involves the elimination of genes from multigene family repertoires by mutations that create nonfunctional pseudogene
s. The color vision priority hypothesis states that the evolution of color vision in primates
may have decreased primate reliance on olfaction, which explains the relaxation of selective pressure that accounts for the accumulation of olfactory receptor pseudogenes in primates.
and Richard Axel
won the Nobel Prize in Physiology or Medicine
for their work on olfactory receptors. In 2006 it was shown that another class of odorant receptors exist for volatile amine
s. This class of receptors consists of the trace amine-associated receptor
s (TAAR) with the exception of TAAR1 which is a receptor for thyronamine
s.
Unfortunately, as with many other GPCRs, there is still a lack of experimental structures at atomic level for olfactory receptors and structural information is based on homology modeling
methods.
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
s of olfactory receptor neuron
Olfactory receptor neuron
An olfactory receptor neuron , also called an olfactory sensory neuron , is a transduction cell within the olfactory system. J. Rospars, Dendritic integration in olfactory sensory neurons: a steady-state analysis of how the neuron structure and neuron environment influence the coding of odor...
s are responsible for the detection of odor
Odor
An odor or odour is caused by one or more volatilized chemical compounds, generally at a very low concentration, that humans or other animals perceive by the sense of olfaction. Odors are also commonly called scents, which can refer to both pleasant and unpleasant odors...
molecules. Activated olfactory receptors are the initial player in a signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
cascade which ultimately produces a nerve impulse which is transmitted to the brain. These receptors are members of the class A rhodopsin-like
Rhodopsin-like receptors
Rhodopsin-like receptors are a family of proteins that comprise the largest group of G protein-coupled receptors.- Scope :G-protein-coupled receptors, GPCRs, constitute a vast protein family that encompasses a wide range of functions...
family of G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
s (GPCRs). The olfactory receptors form a multigene family consisting of over 900 genes in humans and 1500 genes in mice.
Expression
In vertebrateVertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
s, the olfactory receptors are located in the cilia of the olfactory sensory neurons. In insect
Insect
Insects are a class of living creatures within the arthropods that have a chitinous exoskeleton, a three-part body , three pairs of jointed legs, compound eyes, and two antennae...
s, olfactory receptors are located on the antennae
Antenna (biology)
Antennae in biology have historically been paired appendages used for sensing in arthropods. More recently, the term has also been applied to cilium structures present in most cell types of eukaryotes....
and other chemosensory organs. Sperm
Sperm
The term sperm is derived from the Greek word sperma and refers to the male reproductive cells. In the types of sexual reproduction known as anisogamy and oogamy, there is a marked difference in the size of the gametes with the smaller one being termed the "male" or sperm cell...
cells also express odor receptors, which are thought to be involved in chemotaxis
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
to find the egg cell.
Mechanism
Rather than binding specific ligands like most receptorsReceptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
, olfactory receptors display affinity for a range of odor
Odor
An odor or odour is caused by one or more volatilized chemical compounds, generally at a very low concentration, that humans or other animals perceive by the sense of olfaction. Odors are also commonly called scents, which can refer to both pleasant and unpleasant odors...
molecules, and conversely a single odorant molecule may bind to a number of olfactory receptors with varying affinities. Once the odorant has bound to the odor receptor, the receptor undergoes structural changes and it binds and activates the olfactory-type G protein
G protein
G proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
on the inside of the olfactory receptor neuron. The G protein
Heterotrimeric G protein
"G protein" usually refers to the membrane-associated heterotrimeric G proteins, sometimes referred to as the "large" G proteins. These proteins are activated by G protein-coupled receptors and are made up of alpha , beta and gamma subunits, the latter two referred to as the beta-gamma...
(Golf
GNAL
Guanine nucleotide-binding protein G subunit alpha is a protein that in humans is encoded by the GNAL gene.-Further reading:...
and/or Gs
GNAS1
GNAS complex locus, also known as GNAS, is a protein which in humans is encoded by the GNAS gene. The protein encoded by this gene is the stimulatory G-protein alpha subunit , a key component of many signal transduction pathways.- Gene :...
) in turn activates the lyase - adenylate cyclase
Adenylate cyclase
Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
- which converts ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
into cyclic AMP (cAMP). The cAMP opens cyclic nucleotide-gated ion channel
Cyclic nucleotide-gated ion channel
Cyclic nucleotide-gated ion channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various types of cells.- Discovery :...
s which allow calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
and sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s to enter into the cell, depolarizing the olfactory receptor neuron and beginning an action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
which carries the information to the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
.
The primary sequences of thousands of olfactory receptors (ORs) are known from the genomes of more than a dozen organisms: they are seven-helix transmembrane proteins, but there are (as of July 2011) no known structures of any OR. There is a highly conserved sequence in roughly three quarters of all ORs that is a tripodal metal ion binding site , and Suslick
Kenneth S. Suslick
Kenneth S. Suslick is the Marvin T. Schmidt Professor of Chemistry, Professor of Materials Science & Engineering, and Professor of the Beckman Institute for Advanced Science & Engineering at the University of Illinois at Urbana-Champaign...
has proposed that the ORs are in fact metalloproteins (mostly likely with zinc, copper and possibly manganese ions) that serve as a Lewis Acid site for binding of many odorant molecules.
In a recent but highly controversial interpretation, it has also been speculated that olfactory receptors might really sense various vibrational energy-levels of a molecule rather than structural motifs via quantum coherence mechanisms. As evidence it has been shown that flies can differentiate between two odor molecules which only differ in hydrogen isotope (which will drastically change vibrational energy levels of the molecule).
It should be noted, however, that deuteration changes the heats of adsorption and the boiling and freezing points of molecules (boiling points: 100.0C for H20 vs. 101.42 for D20; melting points: 0.0C for H20, 3.82C for D2O), pKa (i.e., dissociation constant: 9.71x10^-15 for H20 vs. 1.95x10^-15 for D2O, cf. Heavy water
Heavy water
Heavy water is water highly enriched in the hydrogen isotope deuterium; e.g., heavy water used in CANDU reactors is 99.75% enriched by hydrogen atom-fraction...
) and the strength of hydrogen bonding. Such isotope effects
Kinetic isotope effect
The kinetic isotope effect is the ratio of reaction rates of two different isotopically labeled molecules in a chemical reaction. It is also called "isotope fractionation," although this term is somewhat broader in meaning...
are exceedingly common, and so it is well known that deuterium substitution will indeed change the binding constants of molecules to protein receptors.
Diversity
There are a large number of different odor receptors, with as many as 1,000 in the mammalian genomeGenome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
which represents approximately 3% of the genes in the genome. However not all of these potential odor receptor genes are expressed and are functional. According to an analysis of data derived from the human genome project
Human Genome Project
The Human Genome Project is an international scientific research project with a primary goal of determining the sequence of chemical base pairs which make up DNA, and of identifying and mapping the approximately 20,000–25,000 genes of the human genome from both a physical and functional...
, humans have approximately 400 functional gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s coding for olfactory receptors and the remaining 600 candidates are pseudogene
Pseudogene
Pseudogenes are dysfunctional relatives of known genes that have lost their protein-coding ability or are otherwise no longer expressed in the cell...
s.
The reason for the large number of different odor receptors is to provide a system for discriminating between as many different odors as possible. Even so, each odor receptor does not detect a single odor. Rather each individual odor receptor is broadly tuned to be activated by a number of similar odorant structures. Analogous to the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, the diversity that exists within the olfactory receptor family allows molecules that have never been encountered before to be characterized. However, unlike the immune system, which generates diversity through in-situ recombination
V(D)J recombination
VJ recombination, also known as somatic recombination, is a mechanism of genetic recombination in the early stages of immunoglobulin and T cell receptors production of the immune system...
, every single olfactory receptor is translated from a specific gene; hence the large portion of the genome devoted to encoding OR genes. Furthermore most odors activate more than one type of odor receptor. Since the number of combinations and permutations
Combinatorics
Combinatorics is a branch of mathematics concerning the study of finite or countable discrete structures. Aspects of combinatorics include counting the structures of a given kind and size , deciding when certain criteria can be met, and constructing and analyzing objects meeting the criteria ,...
of olfactory receptors is almost limitless, the olfactory receptor system is capable of detecting and distinguishing between a practically infinite number of odorant molecules.
Families
A nomenclatureGene nomenclature
Gene nomenclature is the scientific naming of genes, the units of heredity in living organisms. An international committee published recommendations for genetic symbols and nomenclature in 1957. The need to develop formal guidelines for human gene names and symbols was recognized in the 1960s and...
system has been devised for the olfactory receptor family and is the basis for the official Human Genome Project (HUGO
Human Genome Organisation
The Human Genome Organisation is an organization involved in the Human Genome Project, a project about mapping the human genome. HUGO was established in 1989 as an international organization, primarily to foster collaboration between genome scientists around the world...
) symbols for the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s that encode these receptors. The names of individual olfactory receptor family members are in the format "ORnXm" where:
- OR is the root name (Olfactory Receptor superfamily)
- n = an integer representing a family (e.g., 1-56) whose members have greater than 40% sequence identity,
- X = a single letter (A, B, C, ...) denoting a subfamily (>60% sequence identity), and
- m = an integer representing an individual family member (isoformProtein isoformA protein isoform is any of several different forms of the same protein. Different forms of a protein may be produced from related genes, or may arise from the same gene by alternative splicing. A large number of isoforms are caused by single-nucleotide polymorphisms or SNPs, small genetic...
).
For example is the first isoform of subfamily A of olfactory receptor family 1.
Members belonging to the same subfamily of olfactory receptors (>60% sequence identity) are likely to recognize structurally similar odorant molecules.
Two major classes of olfactory receptors have been identified in humans:
- class I (fish-like receptors) OR families 51-56
- class II (tetrapodTetrapodTetrapods are vertebrate animals having four limbs. Amphibians, reptiles, birds and mammals are all tetrapods; even snakes and other limbless reptiles and amphibians are tetrapods by descent. The earliest tetrapods evolved from the lobe-finned fishes in the Devonian...
specific receptors) OR families 1-13
Evolution
The olfactory receptor gene family in vertebrates has been shown to evolve by birth-and-death evolution, whereby new genes within the family are created through genomic events such as gene duplicationGene duplication
Gene duplication is any duplication of a region of DNA that contains a gene; it may occur as an error in homologous recombination, a retrotransposition event, or duplication of an entire chromosome.The second copy of the gene is often free from selective pressure — that is, mutations of it have no...
s or gene conversion
Gene conversion
Gene conversion is an event in DNA genetic recombination, which occurs at high frequencies during meiotic division but which also occurs in somatic cells. It is a process by which DNA sequence information is transferred from one DNA helix to another DNA helix, whose sequence is altered.It is one...
s. Tandem duplications are evidenced by the fact that many olfactory receptor genes belonging to the same phylogenetic clade
Clade
A clade is a group consisting of a species and all its descendants. In the terms of biological systematics, a clade is a single "branch" on the "tree of life". The idea that such a "natural group" of organisms should be grouped together and given a taxonomic name is central to biological...
are located in the same gene cluster
Gene cluster
A gene cluster is a set of two or more genes that serve to encode for the same or similar products. Because populations from a common ancestor tend to possess the same varieties of gene clusters, they are useful for tracing back recent evolutionary history...
. Birth-and-death evolution also involves the elimination of genes from multigene family repertoires by mutations that create nonfunctional pseudogene
Pseudogene
Pseudogenes are dysfunctional relatives of known genes that have lost their protein-coding ability or are otherwise no longer expressed in the cell...
s. The color vision priority hypothesis states that the evolution of color vision in primates
Evolution of color vision in primates
The evolution of color vision in primates is unique compared to most eutherian mammals. A remote vertebrate ancestor of primates possessed tetrachromacy, but nocturnal, warm-blooded, mammalian ancestors lost two of four cones in the retina at the time of dinosaurs...
may have decreased primate reliance on olfaction, which explains the relaxation of selective pressure that accounts for the accumulation of olfactory receptor pseudogenes in primates.
Discovery
In 2004 Linda B. BuckLinda B. Buck
Linda Brown Buck is an American biologist best known for her work on the olfactory system. She was awarded the 2004 Nobel Prize in Physiology or Medicine, along with Richard Axel, for their work on olfactory receptors....
and Richard Axel
Richard Axel
Richard Axel is an American neuroscientist whose work on the olfactory system won him and Linda B. Buck, a former post-doctoral scientist in his research group, the Nobel Prize in Physiology or Medicine in 2004....
won the Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
for their work on olfactory receptors. In 2006 it was shown that another class of odorant receptors exist for volatile amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
s. This class of receptors consists of the trace amine-associated receptor
Trace amine-associated receptor
Trace amine-associated receptors, abbreviated TAAR and otherwise known as trace amine receptors, abbreviated TAR or TA, are a class of G protein-coupled receptors identified in 2001....
s (TAAR) with the exception of TAAR1 which is a receptor for thyronamine
Thyronamine
Thyronamine refers both to a molecule, and to derivatives of that molecule: a family of decarboxylated and deiodinated metabolites of the thyroid hormones thyroxine and 3,5,3'-triiodothyronine .-Types:The group includes:* Thyronamine...
s.
Unfortunately, as with many other GPCRs, there is still a lack of experimental structures at atomic level for olfactory receptors and structural information is based on homology modeling
Homology modeling
Homology modeling, also known as comparative modeling of protein refers to constructing an atomic-resolution model of the "target" protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous protein...
methods.
See also
- ReceptorReceptor (biochemistry)In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
- Trace amine-associated receptorTrace amine-associated receptorTrace amine-associated receptors, abbreviated TAAR and otherwise known as trace amine receptors, abbreviated TAR or TA, are a class of G protein-coupled receptors identified in 2001....
- OdorantAroma compoundAn aroma compound, also known as odorant, aroma, fragrance or flavor, is a chemical compound that has a smell or odor...
- PseudogenePseudogenePseudogenes are dysfunctional relatives of known genes that have lost their protein-coding ability or are otherwise no longer expressed in the cell...
s - Gene familyGene familyA gene family is a set of several similar genes, formed by duplication of a single original gene, and generally with similar biochemical functions...