Model of an odor receptor, a GCPR-receptor. Comparison of the predicted binding sites for GPCRs: white, bovine rhodopsin; green, rat I7 OR; blue, mouse I7 OR; red, β1AR. No clear mechanism is known for the message transmission. A suggestion: After the ligand is bound, the extracellular loop 2 may close down over the barrel. The dramatic movement of EC2 in response to ligand binding may cause helix 3 to translate in the cytoplasmic direction, exposing the D(E)RY sequence to the cytoplasmic region near the G protein. This might initiate the signal transduction pathway, and the involvement of second messenger pathways (amplifying cascade).A sensory input has a 'what is it?', and a quality question 'how' or 'is this good?' and those questions come (almost) together. This is the eg. sensory input and the qualia-problem of that input. How our self interpret that smell. This happens automatically, without any conscious desisionmaking. But is this interpretion in the brain or already in the sensory receptors/neurons? Now the olfactory area in the brain is very near the receptors, so it is perhaps not so big difference. In fact all of our 'big' senses are in our head, seeing, hearing, tasting, smelling. It is only 'touch', or somatic sensory receptors, that is not. Is 'touch' then interpreted in another way than the 'top senses'? Are there a hierarchy in sensory inputs? The outcome is often depending on all senses, but in different degrees. Maybe the different evolutionary sensory ages lies behind that hierarchy? Olfaction sense is very old, says a look at the genes. Also bacterias have the same genes. The function of pseudogenes is also unclear.
'Sensory qualia are assigned to the sensory receptors rather than to the neural circuitry of brain as in standard neuroscience' says Matti Pitkänen. 'The identification of qualia follows from the identification of quantum jump as a moment of consciousness. Just as quantum numbers characterize the physical state, the increments of quantum numbers characterize the quantum jump between two states. This leads to a capacitor model of the sensory receptor in which the sensory perception corresponds to a generalized di-electric breakdown in which various particles carrying some quantum numbers flow between electrodes and the change of the quantum numbers at second electrodes gives rise to the sensory quale.'
Pitkänen has also proposed frequency coding for the sensory qualia. Frequencies code provide only a symbolic representations - define their names - as one might say. The information about qualia and more general sensory data would be represented in terms of cyclotron frequencies inducing dynamical patterns of the cyclotron Bose-Einstein condensates of biologically important ions residing at the magnetic body receiving the sensory information (I talk more of this later).
Quantum biology
'Welcome to the strange new world of quantum biology', says Graham Fleming in 'Is Quantum Mechanics Controlling Your Thoughts?'. 'Quantum mechanics and the biological sciences do not mix. Biology focuses on larger-scale processes, from molecular interactions between proteins and DNA up to the behavior of organisms as a whole; quantum mechanics describes the often-strange nature of electrons, protons, muons, and quarks—the smallest of the small. Many events in biology are considered straightforward, with one reaction begetting another in a linear, predictable way. By contrast, quantum mechanics is fuzzy because when the world is observed at the subatomic scale, it is apparent that particles are also waves: A dancing electron is both a tangible nugget and an oscillation of energy. (Larger objects also exist in particle and wave form, but the effect is not noticeable in the macroscopic world.)'
Is it really so that the worlds don't mix? How sensitive can a receptor be? It is a big protein though. Protons are known to give a respons, but electrons are far to small? Proton-coupled electron transfer (PCET), especially prevalent at metallo-cofactors that activate substrates at carbon, oxygen, nitrogen and sulphur atoms maybe? Those free radicals again.
Different models of olfaction.
The prevailing notion is that the sensation of different smells is triggered when molecules called odorants fit into receptors like 3-D puzzle pieces snapping into place; the key and lock models. When probed by a biological system, shape now translates into the sum total of all the repulsive and attractive interactions that a molecule 'feels' when bound to a receptor: exchange repulsion plus hydrogen bond donors and acceptors, lone pairs, etc.. But molecules with similar shapes do not necessarily smell the same. It is not only a question about 3-D. While odorant shape and size are important, experiment indicates these are insufficient. Isomeri, carbon chain structure, functional and end groups, metals etc. are also important.
One so far speculative model suggests inelastic electron tunneling from a donor to an acceptor mediated by the odorant actuates a receptor, and provides critical discrimination; the swipe card model, or vibrational spectrum of the odorant (Dyson 1938), reproposed by Luca Turin. Recognition and actuation involve size and shape, but also exploit other processes.
Receptors perform an act of quantum tunneling when a new odorant enters the nostril and reaches the olfactory nerve. After the odorant attaches to one of the nerve’s receptors, electrons from that receptor tunnel through the odorant, jiggling it back and forth. In this view, the odorant’s unique pattern of vibration is what makes a rose smell rosy and a wet dog smell wet-doggy.
The vibrational theory has been given the thumbs up by a team of physicists, says a Nature article 2006, Rogue theory of smell gets a boost.
The problem is intensity and background, perception is learned, says Wilson & Stevenson. The psychological side of odors are very poorly known. They say: 'The discovey of a large gene family coding for odor receptors 1991 (Buck & Axel) has led some to conclude that perception happens at the receptor sheet and that knowing of the pattern of the receptors afferent activity will predict the perception.'
Brennan & Kendrick says: Many of these signals take the form of complex mixtures and have important influences on a variety of behaviours, attracting interest and approach, that are vital for reproductive success, such as parent-offspring attachment, mate choice and territorial marking. Chemosignals with relatively high volatility can be used to signal at a distance and are sensed by the main olfactory system. Most mammals also possess a vomeronasal system, which is specialized to detect relatively non-volatile chemosensory cues following direct contact. Single attractant molecules are sensed by highly specific receptors using a labelled line pathway. These act alongside more complex mixtures of signals (based on the highly polymorphic genes of the major histocompatibility complex) that are required to signal individual identity. Thus robust systems for olfactory learning and recognition of chemosensory individuality have evolved, often associated with major life events, such as mating, parturition or neonatal development. In the accessory olfactory bulb, memory formation is hypothesized to involve a selective inhibition. Information is integrated at the level of the corticomedial amygdala, which forms the most important pathway by which social odours mediate their behavioural and physiological effects. Indeed, mammals could also learn odours associated with maternal MHC type in utero.
The receptors
Studies of the relationship between molecular shape and odor were earlier made without reference to the biological sensor. The discovery 1991 that the olfactory receptors were seventransmembrane helix proteins (7-TM), GCPR:s, finally brought this problem into focus.
'Olfactory receptors (GCPR:s) play a key role for a reliable recognition and an accurate processing of chemosensory information,' says Fleischer et.al. in 'Mammalian olfactory receptors'. 'They are therefore considered as key elements for an understanding of the principles and mechanisms underlying the sense of smell. The repertoire of olfactory receptors in mammals encompasses hundreds of different receptor types which are highly diverse and expressed in distinct subcompartments of the nose. Accordingly, they are categorized into several receptor families, including odorant receptors (ORs), vomeronasal receptors (V1Rs and V2Rs), trace amine-associated receptors (TAARs), formyl peptide receptors (FPRs), and the membrane guanylyl cyclase GC-D. This large and complex receptor repertoire is the basis for the enormous chemosensory capacity of the olfactory system.' The olfactory system is composed of several chemosensory subsystems, including the main olfactory epithelium (MOE), the vomeronasal organ (VNO), the septal organ (SO), and the Grueneberg ganglion (GG).
Different olfactory compartments in the nose express distinct types of olfactory receptors. The olfactory receptortypes expressed in each of these organs are indicated by color. The olfactory sensors is building a microsystem map (of the whole body), which is very sensually and 'sexy' ('good/bad').Combinatorial receptor codes for odors
'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. Our studies also indicate that slight alterations in an odorant, or a change in its concentration, can change its "code," potentially explaining how such changes can alter perceived odor quality, say Malnic et.al. Individual olfactory neurons are responsive to qualitatively distinct odor compounds too.
Further, the olfactory system forms a unique spatial organization such that the axons of olfactory neurons expressing the same receptor converge onto fixed glomeruli of the main olfactory bulb (MOB). The type of activated receptors in the olfactory epithelium directly reflect the receptive field in the olfactory bulb, where they provide input to the primary dendrites of mitral and tufted cell projection neurons. Each glomerulus receives input from a single receptor type and therefore acts as a fundamental unit of odour representation. The result is a simple map. Accessory olfactory bulb mitral cells respond selectively to the strain identity of stimulus animals. Significant excitatory responses are indicated in red and significant inhibitory responses are indicated in green, in this fig. That is the 'good' signal is discriminated from the 'bad' already in the bulb, through a 'grid system'. Probabilities and quantum mechanic is used to compute this?
Communication
GPCRs mediate our sense of vision, smell, taste, and somatic sensations. They are also involved in cell recognition and communication processes, and hence have emerged as a prominent superfamily for drug targets. Half the GCPR:s are nonsensory communicative receptors, and mediates diverse physiological stimuli such as light, hormones, and neurotransmitters.
The receptor code for an odorant changes at different odorant concentrations, consistent with our experience. This concentration gradient can perhaps be explained by quantum tunnelling, where a small force give no or just a little transfer of information. See an animation of this. In ordinary biology it is explained by changing receptor sensitivity. 'At a low concentration of the odorant, only the receptor A recognizes the odorant, but at increased concentrations, more receptors can recognize the odorant, implicating that the encoding of the odorant changes at different concentrations.'
According to the old shape theory, discrimination at the level of olfactory receptors correlates with the receptive field in the olfactory bulb in brain, where the input signal is further processed, to create the specific odor maps in brain. The combination of sensory neuron specificity and the pattern of firing activity and the Ca-waves, appears to contribute to reconstruction of the information into a unified conscious perception in the CNS. Apparently, the perception of external signals and the correspondence of those signals in the physical world, is essential for most species across phyla to organize their various behaviors and processes.
Functional responses of single olfactory neurons can be seen in EEG-pattern, when actionpotentials and Ca-waves are generated upon sensing. Once the chemical signal encoded by odorants from the physical world (in the dendritic tree) is converted to electrosignals in the receptor neurons, the information is transmitted as an on-off signal to the glomerulus, the olfactory bulb and ultimately to the olfactory cortex.
But these potentials is made up of many different types of receptors and somatic, reflexive maps in the nose, and of both 'what' and 'good/bad', or 'how', the quality information. In no way the 'good/bad' information can be emergent in the brain. Or can it?
'Although further sharp tuning of the specificity and the integration of signals from odorant receptors may occur in the olfactory bulb and cortex, the pattern created at the peripheral receptor neurons is fairly preserved in the course of signal processing. The receptor code scheme, therefore, plays the main role in contributing to the olfactory processing of odor molecule information', says Touhara 2002. And he continues, 'Since the receptor codes for odorants seem to mainly contribute to odor discrimination, the function of signal transmission in olfactory neurons is mainly to produce action potentials. In this context, it should not be necessary to have more than one signal transduction pathway. Indeed, gene knock-out studies suggested that the cAMP cascade comprised of three components (i.e., stimulatory G protein alpha subunits, adenylyl cyclase type III, and cyclic nucleotide-gated channels). Also IP3 is perhaps used as another pathway (observations of cross-talk between the two pathways = concertations), which would give complex signals. Odorant stimulation results in either excitatory or inhibitory responses of individual olfactory neurons.
Complex signals is suggested by Kaivarainen as a quantum computation tool.
Calcium imaging is another strategy for detecting physiological odorant responses of olfactory neurons by measuring the temporal and spatial properties of Ca2+ changes caused by odorant stimuli. Odorant stimulation causes Ca2+ entry through cyclic nucleotide-gated channels in individual responsive neurons, which is regulated by a series of signal transduction components as well as feedback mechanisms followed by odor adaptation of the activated cells.
Agonist - antagonist in odors
Functional evidence that the olfactory receptors indeed mediate odorant signals had not been provided for many years since the discovery of the superfamily 1991. Heterologous expression systems and the lack of antagonists were the main reasons. The pairing of receptor and ligand was difficult. The chimeric receptor approach has led to the identification of a number of ligands for several olfactory receptors in rats and humans (also taste). In fact are olfactory receptors found through the whole body, not only in the nose. Why? Do other cells too smell? Or can it be the phonon electron tunnelling as Turin suggest?
Despite increasing information on agonist–OR combinations, little is known about the antagonism of ORs in the mammalian olfactory system. Oka et.al. shows how odorants inhibit odorant responses of ORs; evidence of antagonism between odorants at the receptor level. The antagonism was also visualized at the level of the olfactory epithelium. Dual functions of odorants as an agonist and an antagonist to ORs indicate a new aspect in the receptor code determination for odorant mixtures that often give rise to novel perceptual qualities that are not present in each component. The encoding of an odorant quality is determined by a combination of ORs. A receptor code for an odorant mixture, therefore, is expected to be the sum of the codes for its components. The perceived magnitude of an odorant mixture was neither additive nor a simple average of its components, but instead fell between these limits, designated as masking (i.e. modification of perceived odor) or counteraction (i.e. reduction of odor intensity). Mixing some odorants led to the emergency of novel perceptual qualities that were not present in each component, suggesting that odorant mixture interactions occurred. There is evidence that odorant mixture interaction begins at the peripheral neurons. Odorants compete to bind the receptor sites and activate or antagonize olfactory neurons, resulting in a nonadditive receptor code (synergism/suppression). It describes a molecular aspect in the odor-recognition mechanism in the olfactory sensing system that always perceives odorants as a mixture in real life and results in the creation of a complex spatial odor map, which is eventually transmitted to the higher cortical areas of the brain where a conscious perception is constructed. 'Our pharmacological analyses of receptor antagonism in HEK293 cells and single olfactory neurons that expressed a defined OR clearly demonstrated that odorant mixture suppression occurred at the receptor level', says Oka et.al.
Zou et.al. revealed a stereotyped sensory map in the olfactory cortex in which signals from a particular receptor are targeted to specific clusters of neurons. Inputs from different receptors overlap spatially and could be combined in single neurons, potentially allowing for an integration of the components of an odorant's combinatorial receptor code. Signals from the same receptor are targeted to multiple olfactory cortical areas, permitting the parallel, and perhaps differential, processing of inputs from a single receptor before delivery to the neocortex and limbic system.
Also odorant decaying products may be used as antagonists.
Microtubulis computate.
In vision, color discrimination is produced by appropriate combinations of three 'types' of receptors that are each most sensitive to a different part of the visible spectrum (i.e., red, blue, and green). In gustatory sensation, five basic qualities (i.e., bitter, salty, sour, sweet, and umami) are detected by distinct 'classes' of receptors in taste cells. The olfactory system requires highly discriminative capabilities to distinguish thousands of different odorous chemicals. This must happen at receptor level, and be computated by microtubulis. 'Discrimination of various odorants seems to be performed primarily at the receptor level but not at the level of signaling pathways', says Toukara.
More of microtubulis and different frequential windows later.
'It would seem that either we have been blessed with supernatural luck or there is some correspondence between our calculations and odor character', says Turin about the developement of new perfumes (in Rational odorant design). 'What has changed from Dysons years is that we have gained a large database of odors and structures, and a vastly better understanding of the ways in which a ligand can interact with a receptor. What has not changed is our ignorance of the exact structure of the receptor, which makes proper modeling virtually impossible. Trial and error is still the main way to get a new odor. Using computers would be much easier.'
References.
Dyson, G. Malcolm (1938) The scientific basis of odor. Chemistry & Industry 57:647-51
Amoore, John E (1970). Molecular Basis of Odor. Springfield IL: Thomas
Wright, R.H. (1982) The sense of smell CRC press, Boca Raton, Florida, USA
Buck L and Axel R (1991) A novel multigene family may encode odorant receptors: a
molecular basis for odor recognition. Cell. 1991 Apr 5;65(1):175-87.
Turin L. (1996) A spectroscopic mechanism for primary olfactory reception. Chem Senses. Dec;21(6):773-91
Touhara K., 2002: Odor Discrimination by G Protein-Coupled Olfactory Receptors. MICROSCOPY RESEARCH AND TECHNIQUE 58(3):135–141. http://www3.interscience.wiley.com/cgi-bin/fulltext/97515771/PDFSTART
Oka Y. et. al. 2004: Olfactory receptor antagonism between odorants. EMBO J. 2004 January 14; 23(1): 120–126. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1271670/?tool=pubmed
And links in the text.
