It is said that St Jerome remarked of St Hilarion that he had the gift of knowing what sins and vices anyone was inclined to by smelling either the person or their garments. By the same faculty,

he could discern good feelings and virtuous propensities.34 This may, or may not be true: we have no way of knowing. What is true is that dogs can distinguish between the smells of T-shirts worn by non-identical but not by identical twins.

Ca2 . As in vertebrates, Ca2 plays several roles ensuring the deactivation of the photosignal. In addition, PLC is both the target and a regulator (GTPase activator, see page 86) of Gq.31 PKC is a negative regulator of the Ca2 channels, Trp and TrpL (Trp-like, see page 210).

As in vertebrates, the chromophore retinal is an integral component of rhodopsin, but with the difference that it remains attached to the opsin throughout the cycle of activation and recovery. Following illumination by blue light (below 490 nm), the retinal undergoes rapid isomerization to the all-trans form and the resulting metarhodopsin catalyses guanine nucleotide exchange on Gq. The retinal remains firmly attached and the activated metarhodopsin is so stable that it would have a half-life of more than 5 h.32,33 This would not be much help to flies but for the fact that phosphorylation and then the binding of arrestin sensitizes the system to a second photon, this one of longer wavelength (580 nm, orange). This triggers the reinstatement of 11-cis-retinal.

Is not Vision perform’d chiefly by the Vibrations of this medium, excited in the bottom of the Eye by the Rays of Light, and propagated through the solid, pellucid and uniform Capillamenta of the optick Nerves into the place of Sensation? And is not Hearing perform’d by the Vibrations

either of this or some other Medium, excited in the auditory Nerves by the Tremors of the Air, and propagated through the solid, pellucid and uniform Capillamenta of those Nerves into the place of Sensation? And so of the 0ther Senses.

Sir Isaac Newton, Opticks

Olfaction

The human olfactory system is capable of sensing and distinguishing several hundred different molecules (odorants) and a seemingly limitless number of different smells (effectively, combinations of odorants). All of these compounds are volatile, none has a molecular weight much greater than 300 and all have the ability to partition between lipid and aqueous phases. The human olfactory epithelium is formed from 6 million olfactory receptor neurons (ORNs; 50 million in the rat), together with the supporting cells of Bowman’s glands that secrete mucus into the upper reaches of the nasal cavity (Figure 6.14). The dendrites of the receptor neurons terminate as whiplike ciliary extensions, 30–200  m long and 20 on each cell, bearing the

odorant receptors which project into the mucus layer lining the upper reaches of the nose. These dendritic terminations represent the single point at which cells of the central nervous system are exposed to the environment outside the body.

Fig 6.14  Olfactory apparatus, schematic view.

Olfactory receptor cells

The ORNs are bipolar cells. Their single axons project into the olfactory bulbs (extensions of the forebrain, one located above each nasal cavity), where they terminate in glomeruli. These are spherical bundles 50–100  m in diameter, composed of neuronal and glial processes (known as neuropil). Regardless of their location on the surface of the nasal epithelium, the axons of ORNs bearing the same receptor are gathered together and cross the cribriform plate, terminating in a single glomerulus within the bulb. Here they form synapses with the dendrites of a much smaller number of mitral cells. These are the most numerous cells in the bulb (,50 000) and they interact laterally with each other and with other cells. It is in this layer that the inputs of individual ORNs are integrated. The axons of the mitral cells form the lateral

olfactory tract that conveys signals to the primary olfactory cortex in the brain (Figure 6.14 ). The convergence is such that a single mitral cell may receive input from ,1000 ORNs. This means that although the amount of transmitted information is reduced, a very high sensitivity is ensured.

Each day large numbers of ORNs must be replaced and each one of these must be correctly wired up to its own specific target glomerulus. It is evident that the receptors, in addition to providing the means of chemoperception, themselves provide the signals that guide the axons through the maze

to their individual target glomeruli. Thus, in mice engineered to express a

Mitral: pertains to the form of a mitre, a bishop’s hat.

The failure to express pseudogenes may arise from frameshifts, nonsense mutations, or

deletions. This may be the basis of our inferior sense of smell in comparison with other animals (possibly compensated to some degree by visual and auditory senses). The considerable diversity

in olfactory perception among humans may be due to individuals having different non-expressible pseudogenes.35

Linda Buck and Richard Axel were awarded the Nobel Prize in 2004

for their discoveries of ‘odorant receptors and the organization of the olfactory system’.

defined receptor coupled to an axonal marker (coloured blue in the image shown in Figure 6.15), it was found that the axons project to specific pairs of glomeruli, situated symmetrically in each of the olfactory bulbs.35,36

Olfactory receptors

The odorant receptors are 7TM structures, collectively forming by far the largest subgroup of the rhodopsin-like class of receptors37,38 (see Figure 3.14, page 61). In mammals, the odorant receptors are coded by 1000 genes and comprise by far the largest single family in the genome (though in humans a considerable proportion, about 60%, are pseudogenes, and are not transcribed). Within this family the sequence identity ranges from less than 40% to over 90% (near identity). Certain features, such as the elongated second extracellular loop ( 35 residues), appear to be characteristic of

this particular class of receptor (see Figure 6.16). Indeed, within the class, the sequence of this stretch is highly conserved, a feature not shared by the pair of transmembrane helices to which it is linked. Lacking the possibility of carrying out the ligand-binding experiments that have played such an important role in classical pharmacology, clues such as this have been exploited to indicate the zones responsible for odorant binding in these receptors. Indeed, it has been speculated that hypervariable regions in transmembrane spans D, E, and F may form the sites of odorant attachment. There is no reason to think that the olfactory receptors possess the high specificity towards their ligands characteristic of most other receptors. In general, it appears that they can bind multiple odorants of related structure and that most odorants are capable of activating several different receptors to varying degrees. Thus, different odorants activate different sets of glomeruli.39

Transduction of olfactory signals

The sequence of events following activation of these receptors by odorants both resembles and differs from the signalling sequence that operates in vertebrate phototransduction. Of course, the most obvious difference is that these receptors are activated conventionally, by the binding of the

incoming ligands, while rhodopsin is activated when 11-cis-retinal, effectively a resident inverse agonist, is displaced. The activated odorant receptors interact with Golf, a G protein closely related to Gs that activates the Ca2 - calmodulin-sensitive adenylyl cyclase 3 (see Table 5.1, page 138). The cAMP formed interacts with a cyclic nucleotide-gated (CNG) channel, allowing it to conduct Na and Ca2 ions into the cell. Unlike the cGMP-regulated channel in the retina, which is relatively unresponsive to cAMP, the olfactory channel is equally responsive to both nucleotides. Also, unlike the ion channel of photoreceptor cells, the olfactory channel in the retina opens in response to cyclic nucleotides, causing the cells to depolarize. Cloning of CNGs has shown that they are closely related and probably share common ancestry with the superfamily of voltage-regulated ion channels. As the membrane potential drops below 20 mV, the cell generates an action potential which is conveyed along the axon into the specific glomerulus in the olfactory bulb. From here, the signal is conveyed by the mitral cells to the higher centres.

As with the mechanism of phototransduction, the olfactory process allows enormous amplification of the initial signal. A collision of an odorant molecule with its receptor can activate many molecules of Golf. Each of these will activate a single molecule of adenylyl cyclase that can generate large amounts of cAMP. In isolated ciliary membranes, this becomes apparent within 25 ms of applying an odorant and peaks within 500 ms,40 although recorded odorant-induced membrane currents occur after a latency of several hundreds of milliseconds. Some odours, particularly those of a fruity or floral nature, are effective when applied as solutes at concentrations as low as

Although olfactory and retinal CNGs share more than 80% sequence identity in their cyclic nucleotide binding sites, their channel properties are very different. The olfactory channels hardly discriminate between cAMP and cGMP whereas the retinal channels have a much higher affinity for cGMP. The olfactory channel has a larger pore size, a higher single channel conductance and a lower degree

of selectivity among monovalent cations.38

The olfactory receptor neurons contain a highly specialized isoform of phosphodiesterase having high affinity for Ca2 (KM 1.4  mol L 1). More than this, it has a higher affinity for cAMP than any other brain isoform.42 Thus, the binding of odorants to receptors not only initiates the cAMP signal pathway, but also signals its termination.

10 nmol L 1. Others, particularly those with a putrid smell, have no effect in this isolated ciliary membrane preparation and it is thought that these may utilize an additional pathway involving -subunits derived from Go and a Ca2 signal derived from the production of IP3.41

Similar to the channels in the retinal rod outer segment membranes, three molecules of cyclic nucleotide are required to open a CNG and this allows hundreds of thousands of ions to enter the cell. A single odorant molecule is capable of inducing a measurable electrical signal, although the synchronous stimulation of several receptors is probably needed to generate a sensation of smell.

cAMP is certainly the main second messenger that mediates the early stages of odorant perception (Figure 6.17). To illustrate this, adenylyl cyclase 3 knock-out mice cannot smell43 (said to be anosmic). They are insensitive to odorants that induce signals, mediated by phospholipase C

and protein kinase C, that activate adenylyl cyclase 3 (see Table 5.1). However, the signals induced by cAMP are certainly affected by Ca2 and by cGMP. The effects of Ca2 are complex, as it plays a part in the enhancement, modulation, and termination of the odorant-induced signals. As with the retinal system, Ca2 -calmodulin rapidly acts to decrease the affinity of