The cell biology of smell

Abstract

The olfactory system detects and discriminates myriad chemical structures across a wide range of concentrations. To meet this task, the system utilizes a large family of G protein-coupled receptors-the odorant receptors-which are the chemical sensors underlying the perception of smell. Interestingly, the odorant receptors are also involved in a number of developmental decisions, including the regulation of their own expression and the patterning of the olfactory sensory neurons' synaptic connections in the brain. This review will focus on the diverse roles of the odorant receptor in the function and development of the olfactory system.

Figure 1.

Anatomy of the rodent peripheral olfactory system. (A) Schematic representation of a parasagittal section through adult mouse head. Axons of the OSNs in the main olfactory epithelium comprise the olfactory nerve and innervate the olfactory bulb. Vomeronasal sensory neurons project their axons via a separate tract, the vomeronasal nerve, to innervate the accessory olfactory bulb. (B) Each OSN of the main olfactory epithelium expresses only one odorant receptor gene (OR A, OR B, OR C, etc.) out of a repertoire of over 1,000 genes. Neurons expressing a given OR are organized into broad zones along the dorsal–ventral axis of the olfactory epithelium (OE) and converge to a common glomerulus at corresponding dorsal–ventral zones in the olfactory bulb (OB). Each glomerulus thus receives innervation from sensory neurons expressing a single odorant receptor, providing the anatomical basis of the olfactory sensory map.

Figure 2.

Signal transduction in the OSN. (A) Representation of the receptors, enzymes, and ion channels—present in the olfactory cilia—that transduce activity of the odorant receptor (OR) into changes in membrane potential and gene expression. Binding of an odorant to its cognate OR results in the activation of heterotrimeric G protein (Gαolf plus Gβγ). Activated Gαolf in turn activates type III adenylyl cyclase (AC3), leading to the production of cyclic AMP (cAMP) from ATP. cAMP gates or opens the cyclic nucleotide-gated (CNG) ion channel, leading to the influx of Na⁺ and Ca²⁺, depolarizing the cell. This initial depolarization is amplified through the activation of a Ca²⁺-dependent Cl⁻ channel. In addition, cAMP activates protein kinase A (PKA), which can regulate other intracellular events, including transcription of cAMP-regulated genes. (B) Events in the nucleus of OSNs important for establishing and maintaining sensory neuron identity. Selection of a particular OR gene by the cell is thought to occur via interaction of a cis-regulatory locus control region with the proximal promoter of a single OR gene within a cluster of OR genes. This choice is stabilized—and the expression from all other OR genes in the genome is silenced—by an OR-dependent feedback loop, which ensures the expression of a single OR per sensory neuron. The mechanism underlying OR-mediated, OR gene silencing is at present not understood. OR-mediated activity also leads to transcriptional regulation of cAMP response element binding protein (CREB)–dependent gene expression via CREB's phosphorylation by PKA.

Figure 3.

Combinatorial coding of olfactory information. Graphic representation of the olfactory receptor combinatorial code. In this hypothetical example, the responses of five odorant receptors to seven odorants (a–g) are shown, with the magnitudes of responses proportional to the sizes of the circles. Reflecting functional studies on individual odorant receptors, some receptors are more narrowly tuned than others, and individual odorants can activate different subsets (and numbers) of receptors. The pattern of receptor activation elicited by a particular compound is thought to represent that compound's chemical identity.

Figure 4.

Targeting of OSN axons to the olfactory bulb. The projection of OSNs in the olfactory epithelium (OE) to their target glomeruli in the olfactory bulb (OB) can be considered along the bulb's three principal axes. (A) Zone-to-zone projection along the dorsal–ventral axis is shaped in part by complementary gradients of the chemorepellent molecules Slit1 and Semaphorin3F (Sema3F) and their receptors Robo2 and Neuropilin2 (Nrp2), respectively. (B) Innervation of the lateral olfactory bulb is dependent on IGF signaling, which may function to counteract a default tendency of all olfactory neurons to project medially. (C) Projection of olfactory sensory axons along the olfactory bulb's anterior–posterior axis depends not on the position of the cell in the OE, but rather on the level of intracellular cAMP, which in turn regulates the expression of the axon guidance receptor Neuropilin1 (Nrp1). By modulating the expression levels of axon guidance receptors such as Nrp1, the sensory axons are either more or less sensitive to guidance cues found in the OB or along the projection pathway.