A Sense of Smell: Olfactory Receptors

 
The sense of smell in vertebrates is mediated by proteins called olfactory receptors (OR). In the case of mammals, these proteins are embedded in the membranes of sensory neurons in the nasal cavity. Each neuron is thought to contain a single type of olfactory receptor responding to a single type of odorant.

When an odorant binds to the outside of the olfactory receptor it transmits a signal to the interior of the cell. This signal triggers a response that excites the neuron and causes it to pass a message back along the axon to the brain. The brain then interprets the excitation as a specifc odor.

Olfactory receptors belong to a class of proteins called G-protein coupled receptors (GPCR). These proteins possess a characteristic bundle of seven membrane-spanning α-helices forming a tube within the membrane. The binding site for the specific odorant is located within the tube.

It has not been possible to crystallize any of the GPCR's that have been identified but the structures of some similar proteins are known. This enables workers to predict the structure of olfactory receptors using computer models. The models are then tested in various ways to confirm the predictions. We have a pretty good idea of what the olfactory receptors look like.

An example is shown in the figure on the left from a paper by Hall et al. (2004). This is the predicted structure of a mouse olfactory receptor that binds octanol. (Octanol is a sweet-smelling alcohol.) The bound molecule is shown as a red stick model in the side view (left) and the top view (right). The outside of the cell is at the top and that's where the odorant penetrates to the binding site.

The seven coils that you see in the structure are the seven α-helices that span the membrane. When the odorant binds, it changes the structure of the protein a little bit and this slight change includes the part of the receptor at the bottom, which is inside the cell. The change is enough to affect the binding of another protein, called a G-protein. This is what triggers the response.

Many different kinds of receptors activate a signalling pathway in the same manner as the olfactory receptors. A typical example is shown in the diagram below. In this case the signal is triggered by a hormone, but the same principle applies to signals triggered by odorants.


Look at the stimulatory pathway on the left. This is how the olfactory receptors work. When an odorant binds, the conformational change is transmitted through the receptor (R_s) to the inside surface of the membrane. G-protein (green) normally binds to the bottom surface of the receptor but when the receptor is triggered, G-protein is released and moves over to bind to another membrane protein called adenylate cyclase. The release and movement of G-protein is coupled to exchange of GDP for GTP. (GTP is a nucleotide like ATP. The proteins are called G-proteins because they bind GDP/GTP.)

Adenlyate cyclase is an enzyme that catalyzes the conversion of ATP to cyclic AMP (cAMP). cAMP in turn activates an enzyme called protein kinase A. Kinases are enzymes that attach phosphate groups to proteins. In this case, protein kinase A phosphorylates a protein within the neurons converting it from an inactive to an active form. Eventually the signal is transmitted to membrane pumps that are stimulated to alter the flow of charged ions into and out of the cell. This results in an action potential that passes up the axon to the brain.

This is a classic signal transduction pathway. The example shown in the figure is a simplified version with only a single protein kinase phosphorylation. In most cases there is a cascade of phosphorylations (and dephosphrylations) involving a number of different proteins. The study of signal transduction cascades is a major focus of hundreds of biochemistry labs.

The net result of all this biochemistry is that the presence of an odorant in your nose will eventually cause your brain to recognize it, as long as you have a receptor for that odorant. We have 388 different olfactory receptors so we can detect lots of different smells, including cat urine. Mice have 1037 different olfactory receptors so they can probably smell things that we can't. Maybe they can smell cats directly.

The olfactory receptor genes were discovered by Linda Buck and Richard Axel in 1991. They got the Nobel Prize in 2004 (see tomorrow's "Nobel Laureates").

The evolution of these genes in vertebrates raises some interesting questions about mechanisms of evolution. We'll learn about birth-and-death evolution later on this week.

Hall, S., Floriano, W.B., Vaidehi, N. and Goddard III, W.A. (2004) Predicted 3-D Structure for Mouse 17 and Rat 17 Olfactory Receptors and Comparison of Predicted Odor Recognition Profiles with Experiment. Chem. Senses 28: 595-616.