Cellular and molecular constituents of olfactory sensation in vertebrates

doi:10.1016/S1095-6433(00)00191-4

Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology

Volume 126, Issue 1, May 2000, Pages 17-32

https://doi.org/10.1016/S1095-6433(00)00191-4 Get rights and content

Abstract

Since the discovery of odorant-activated adenylate cyclase in the olfactory receptor cilia, research into the olfactory perception of vertebrates has rapidly expanded. Recent studies have shown how the odor discrimination starts at the receptor level: each of 700–1000 types of the olfactory neurons in the neural olfactory epithelium contains a single type of odor receptor protein. Although the receptors have relatively low specific affinities for odorants, excitation of different types of receptors forms an excitation pattern specific to each odorant in the glomerular layer of the olfactory bulb. It was demonstrated that adenosine 3′,5′-cyclic monophosphate (cAMP) is very likely the sole second messenger for olfactory transduction. It was also demonstrated that the affinity of the cyclic nucleotide-gated channel for cAMP regulated by Ca²⁺/calmodulin is solely responsible for the adaptation of the cell. However, many other regulatory components were found in the transduction cascade. Regulated by Ca²⁺ and/or the protein-phosphorylation, many of them may serve for the adaptation of the cell, probably on a longer time scale. It may be important to consider the resensitization as a part of this adaptation, as well as to collect kinetic data of each reaction to gain further insight into the olfactory mechanism.

Introduction

Chemical senses developed in the most ancient animals to detect food, danger, or fellows in their environment, and mammals can discriminate between more than 10 000 types of odors. Research into these ancient sensations became very active no more than two decades ago. cAMP has been generally accepted as the intracellular (second) messenger in the main olfactory receptor cells. Although the hypothesis that inositol 1,4,5-tris-phosphate (IP₃) is an alternative second messenger was prevalent for some time (reviews: Breer and Boekhoff, 1992, Breer et al., 1994, Restrepo et al., 1996, Schild and Restrepo, 1998), it seems to have abated recently (Gold, 1999). This development was strongly driven by molecular biology, which has been powerful for studying not only the subcellular events but also the nerve connections. The mechanism for interconnection between olfactory nerves and the central nervous system (CNS) remains to be elucidated. It will probably be one of the first examples of information processing in the CNS being unveiled and explained through nerve interconnections. In this paper, recent progress in the physiology of the olfactory receptor neurons will be reviewed together with a brief sketch of the molecular biology of the components of olfactory transduction.

Section snippets

Distribution of olfactory receptors in the olfactory epithelium and olfactory bulb

A vertebrate has 2×10⁶–3×10⁸ olfactory cells (Fig. 1) depending on the species, in the olfactory epithelium in the nasal cavity (e.g. Takagi, 1989). Each receptor cell has a single dendrite and an axon extending from its central soma. The apical part of the dendrite is a little swelling called the ‘olfactory knob’, from which five to 20 cilia extend into the mucus on the epithelium. The axon is connected to one of the 100–2000 glomeruli in the olfactory bulb in the central nervous system (CNS),

Transduction mechanism in olfactory cells

The history of research on cAMP as the second messenger in the sensory receptor cells originated with the hypothesis that cAMP might be the second messenger for visual photo-transduction (Bitensky et al., 1972). In early experiments that confirmed the photo-induced shift in cGMP concentration in visual cells, the odor-induced shift in cAMP concentration in olfactory neurons was examined in vain (Bitensky et al., 1972), while a strong activity of adenylate cyclase was detected (Kurihara and

Odorant receptor

Characteristics of the odorant receptors are the main concern in this section. In an early trial, mRNA collected from olfactory receptors was directly injected into the Xenopus oocyte, which provided some suggestive data for the receptor protein (Getchell, 1988). Later, as described before, the PCR technique demonstrated the existence of the putative odorant receptors, although the protein itself was not detected. Those amino acid sequences appeared to have seven hydrophobic transmembrane

G-protein

The odor-induced increase of cAMP at the olfactory cilia was first detected by supplying GTP to the reaction mixture (Pace et al., 1985). Like other 7-transmembrane domain receptors, odorant receptors interact with G-proteins named G_olf (Jones and Reed, 1989) to activate the enzymatic cascade. G_olf is similar to, but distinct from G_s that operates in other systems such as hormone receptors. When the receptor is activated to interact with α subunit of G-protein (G_α), GDP on this subunit is

Nucleotide cyclase

After the re-discovery of adenylate cyclase in olfactory cells (Pace et al., 1985), rapid formation of cAMP in subsecond order was demonstrated (Breer et al., 1990), which provided the basis of the fast transduction process. After a report that some odorants did not activate AC (Sklar et al., 1986), it was demonstrated that odorants activate either AC or phospholipase C (PLC) alternatively (Boekhoff et al., 1990). However, this interpretation seems to have been revised: The odor-induced cAMP

Phosphodiesterase

In the olfactory cilia, there are two kinds of phosphodiesterase (PDE) having low K_m for cAMP, CAM-PDE (or PDE1C2)(Borisy et al., 1992, Yan et al., 1995, Yan et al., 1996) and cAMP-PDE (or PDE4A) (Borisy et al., 1993). CAM-PDE can hydrolyze both cAMP and cGMP. Its activity is enhanced 6 times by the Ca²⁺ entering through the CNG channels in the presence of calmodulin (Borisy et al., 1992). When cAMP is increased by the odor stimulus, PKA is activated to phosphorylate this CAM-PDE. The

Phosphorylation of receptor

Generally, phosphorylation of the G-protein coupled receptor causes the G-protein to separate from the receptor, leading to the inactivation of the whole cascade. A similar mechanism may operate in olfactory transduction. Phosphorylation of 50 kD proteins in the olfactory cilia was first detected, and this protein was evidenced to be the odorant receptor (Krieger et al., 1994). Protein kinase and receptor kinase for this phosphorylation are detected in different types of tissues. In the

CNG-channel

CNG channels of olfactory cells have a higher affinity for cyclic nucleotides than those of photoreceptor cells, and they have a higher affinity for cGMP than cAMP: Their K_1/2s for cAMP and cGMP are ca. 3 and ca. 2 uM, respectively, in the low divalent cation solution. As the channels respond to cGMP, the possibility that cGMP has some physiological role in olfactory transduction has been considered. However, the change of cGMP is not so large or fast. It may be related to the adaptation

Ca²⁺-activated Cl^- channel

A conductance with a similar size to CNG-channels in the olfactory cilia is attributed to Ca²⁺-activated Cl⁻ channels, K_m of which for Ca²⁺ is about 5 uM (Kleene and Gesteland, 1991). It is specifically permeable for anions, with a preference for Cl⁻: the order of permeability is P_Cl>P_F>P_I>P_Br, and the ratio of permeability to Na (P_Na/P_Cl) is 0.034. It is also permeable for larger organic anions with a permeability sequence of P_Cl>P_SCN>P_acetate>P_gluconate (Hallani et al., 1998). The pore

Ca²⁺

As we have reviewed in the above sections, Ca²⁺ has a controlling role in many steps of the transductory cascade. Therefore, measurements of the concentration and movement of Ca²⁺ are important. Developments of Ca²⁺ sensitive dyes and imaging technology have made this research very active.

The most detailed study of the dynamic change of Ca²⁺ concentration in olfactory receptor cells was performed by Leinders-Zufall et al., 1997, Leinders-Zufall et al., 1998. Although many reports (Restrepo and

IP₃

Many discussions in this decade have asserted that IP₃ is an alternative second messenger for the olfactory transduction in vertebrate. Recent reviews argued for (Schild and Restrepo, 1998) or against (Gold, 1999) the proposed role of IP₃. Details can be found in those articles. The arguments will be briefly described here, and some additional discussion will be offered.

The argument started from reports that some odorants did not induce the increase of cAMP (Sklar et al., 1986), but instead

Gaseous messenger

The high affinity of the CNG channel for cGMP has been puzzling, as the major portion of olfactory cells do not have distinct cGMP cascade. At first, it was proposed that NO produced by NO-synthase (NOS) stimulates sGC to produce cGMP (Breer et al., 1992). However, NOS is dominant in olfactory cells only during developmental or regenerating stages, which suggests that the NO-cGMP cascade is related to guiding axon terminals to form synapses (Roskams et al., 1994) as predicted by Zufall et al.

For further study

The research into olfactory cells has been carried out by a combination of electrophysiology, biochemistry, histochemistry and molecular biology. Molecular biology has been especially powerful for analyzing not only the subcellular events, but also the higher order subjects such as axon interconnections. One of the recent examples is the study of olfactory marker protein (OMP) whose function has been elusive for long time. It was shown by the use of knock out mice, that the OMP is related to

Acknowledgements

The author thanks Drs B. Lindemann, Y. Koutalos and K. Touhara for their critical readings of the manuscript, and H. Kaneko for his help in the preparation of the figures. This work was done while the author was staying in Dr B. Lindemann’s laboratory as an Overseas Research Scholar of the Ministry of Education, Science, Sports and Culture of Japan. This article is dedicated to the memory of Dr Geoffrey H. Gold.

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ReviewCellular and molecular constituents of olfactory sensation in vertebrates

Abstract

Introduction

Section snippets

Distribution of olfactory receptors in the olfactory epithelium and olfactory bulb

Transduction mechanism in olfactory cells

Odorant receptor

G-protein

Nucleotide cyclase

Phosphodiesterase

Phosphorylation of receptor

CNG-channel

Ca2+-activated Cl- channel

Ca2+

IP3

Gaseous messenger

For further study

Acknowledgements

Neuron

Trends Cardiovasc. Med.

J. Biol. Chem.

J. Biol. Chem.

Brain Res.

Curr. Opin. Neurobiol.

Biochim. Biophys. Acta

Neuron

Cell

Biophys. J.

Cell

Neuron

Neurosci. Lett.

Trends Pharmacol.

Cell

J. Neurosci. Methods

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Comp. Biochem. Physiol.

Neurosci. Lett.

Cell

Biochem. Biophys. Res. Commun.

Neuron

Biophys. J.

FEBS Lett.

Cell

FEBS Lett.

Neurosci. Lett.

Biophys. J.

Neurosci Lett

Neurochem. Int.

J. Biol. Chem.

Cell

Cell

Identification of a specialized adenylyl cyclase that may mediate odorant detection

Science

Concentration dependence of sodium permeation and sodium ion interactions in the cyclic AMP-gated channels of mammalian olfactory receptor neurons

J. Membr. Biol.

The role of cyclic AMP in visual excitation

Adv. Cyclic Nucleotide Res.

Odor-induced phosphorylation of olfactory cilia proteins

Proc. Natl. Acad. Sci. USA

Rapid activation of alternative second messenger pathways in olfactory cilia from rats by different odorants

EMBO J.

The native rat olfactory cyclic nucleotide-gated channel is composed of three distinct subunits

J. Neurosci.

Calcium/calmodulin-activated phosphodiesterase expressed in olfactory receptor neurons

J. Neurosci.

Functional expression of the heteromeric ‘olfactory’ cyclic nucleotide-gated channel in the hippocampus: a potential effector of synaptic plasticity in brain neurons

J. Neurosci.

Rapid kinetics of second messenger formation in olfactory transduction

Nature

Nitric oxide mediated formation of cyclic GMP in the olfactory system

Neuroreport

Direct modulation by Ca2+-calmodulin of cyclic nucleotide-activated channel of rat olfactory receptor neurons

Nature

Molecular biology of smell: expression of the multigene family encoding putative odorant receptors

Cold Spring Harb. Symp. Quant. Biol.

Ionic composition of toad olfactory mucus measured wsith ion selective microelectrodes

Chemical Senses

Salamander olfactory bulb neuronal activity observed by video rate, voltage-sensitive dye imaging. III: spatial and temporal properties of responses evoked by odorant stimulation

J. Neurophysiol.

Review
Cellular and molecular constituents of olfactory sensation in vertebrates

Ca²⁺-activated Cl^- channel

Ca²⁺

IP₃

Direct modulation by Ca²⁺-calmodulin of cyclic nucleotide-activated channel of rat olfactory receptor neurons