The sense of smell, or olfaction, allows for the detection and discrimination of thousands of chemical compounds, known as odorants. Olfactory receptors are the molecular machinery responsible for translating this chemical stimulus into an electrical signal the brain can interpret. Understanding receptor activation requires examining the sequence of molecular events within the sensory cell. This article details the steps, from the location of these receptors to the final electrical signal generation and the mechanisms that shut the response down.
The Cellular Environment
The initial activation of olfaction takes place deep within the nasal cavity in the olfactory epithelium. Embedded within this tissue are millions of olfactory sensory neurons (OSNs). Each OSN extends a single dendrite that terminates in a dendritic knob at the surface of the epithelium.
From this knob, numerous non-motile, hair-like projections called cilia extend outward and are covered in a layer of mucus. These cilia are the primary sites of odorant detection. The olfactory receptor proteins are embedded within the plasma membrane of these cilia, positioning them to encounter odorant molecules dissolved in the overlying mucus layer.
Odorant Binding and Receptor Specificity
The olfactory receptors belong to the largest family of proteins in the vertebrate genome, known as G-protein Coupled Receptors (GPCRs). These proteins span the cell membrane seven times, creating an internal binding pocket for the odorant molecule. In humans, there are approximately 400 functional types of these receptors, which collectively detect a vast variety of smells.
The initial interaction follows a lock-and-key principle, where the odorant’s shape and chemical properties determine receptor binding. This relationship is not strictly one-to-one: a single odorant can activate a subset of different receptors, and one receptor can be activated by several odorants. This combinatorial activation pattern allows the limited number of receptor types to encode the massive diversity of odors perceived.
The G-Protein Cascade
Odorant binding causes a change in the receptor’s shape, activating an intracellular signaling cascade. This conformational shift allows the receptor to interact with the specialized trimeric G-protein complex known as G-olf. G-olf is inactive when bound to guanosine diphosphate (GDP). The activated receptor promotes the exchange of GDP for guanosine triphosphate (GTP) on the G-olf alpha subunit.
The G-olf alpha subunit detaches and activates a membrane-bound enzyme called adenylyl cyclase (ACIII). Adenylyl cyclase catalyzes the conversion of adenosine triphosphate (ATP) into the second messenger, cyclic adenosine monophosphate (cAMP).
Multiple cAMP molecules then bind to cyclic nucleotide-gated (CNG) ion channels embedded in the ciliary membrane. The binding of cAMP opens the CNG channels, allowing a rapid influx of positive ions, primarily calcium (\(\text{Ca}^{2+}\)) and sodium (\(\text{Na}^{+}\)), into the neuron. This influx of positive charge causes depolarization, changing the electrical potential across the cell membrane.
The rise in intracellular \(\text{Ca}^{2+}\) also triggers the opening of calcium-activated chloride channels, causing a chloride ion efflux that further contributes to depolarization. This depolarization generates an action potential that travels from the olfactory sensory neuron to the olfactory bulb in the brain, conveying the odor perception.
Signal Termination
The olfactory system must quickly reset to respond to new stimuli, requiring rapid termination of the activation signal. One primary mechanism for signal shut-down involves the rapid breakdown of the second messenger, cAMP. Enzymes called phosphodiesterases (PDEs), such as PDE1C, are localized within the olfactory cilia and hydrolyze cAMP back into inactive AMP.
The influx of \(\text{Ca}^{2+}\) during activation also plays a direct role in negative feedback. Calcium ions bind to the protein calmodulin, forming a \(\text{Ca}^{2+}\)-calmodulin complex. This complex binds directly to the CNG channels, reducing their sensitivity to cAMP, which promotes channel closure and stops the flow of positive ions.
Furthermore, the \(\text{Ca}^{2+}\)-calmodulin complex can activate \(\text{Ca}^{2+}\)-calmodulin-dependent protein kinase II (\(\text{CaMKII}\)). \(\text{CaMKII}\) can phosphorylate and inhibit adenylyl cyclase, reducing the production of new cAMP. These mechanisms ensure the olfactory neuron quickly returns to its resting state, preparing it for the next incoming odorant stimulus.