The olfactory system is capable of recognizing and discriminating between a staggering number and variety of odorants, which are primarily small organic molecules. It performs this task over many orders of concentration and with complex blends of chemicals as well as mono-molecular compounds. We now have a reasonable description of how the peripheral olfactory system achieves at least the first part of the task – binding of odorants to receptors and transducing this to an electro-chemical signal that is transmitted to higher centers in the brain. Here I will concentrate on the large family of receptors in the peripheral tissues and the interactions between these receptors and the many different odorant compounds.
As with other receptors of the GPCR type, these receptors bind their cognate ligands in a pocket that appears to be 1/3 or more of the way into the membrane spanning region of the molecule. Precisely how different receptors discriminate between different compounds is not entirely understood, but the large number of both receptors and ligands provides an unparalleled opportunity to understand this interaction at the level of pharmacology.
Most intriguingly is the possibility that odors not only activate a receptor, but may also modulate receptor activity by having antagonist or partial agonist activity. Thus in a complex blend the same molecule may act as an agonist for some receptors and an antagonist at other receptors – thus significantly complicating the nature of the signal being transmitted to the brain.
The olfactory receptors themselves account entirely for the phenotype of the olfactory sensory neurons. There are more than 1000 receptor genes in the mouse (450 in the human) and each olfactory sensory neuron chooses only one of these genes for expression. The choice of this gene determines entirely which ligands the cell will recognize and respond to. Additionally the choice of receptor determines the target of the sensory neuron axon in the olfactory bulb. Axons from all sensory neurons expressing the same receptor coalesce into a single structure known as a glomerulus where they make synapses with the second order projection neurons of the olfactory bulb. These glomeruli are specific for a particular receptor. Thus the receptor defines not only the ligand that the cell will recognize but also the target for its axon in the central nervous system.
This organization leads to interesting relations between development and function that will be considered.
Research Activities :
Honors and Awards :
- 2009: College of Reviewers, NIH
- 2006: Columbia University Press, editorial board
- 2011: Advisor for the Alfred P. Sloan Foundation’s program for the Public Understanding of Science
- 2011: Lenfest Award for Distinguished Teaching and Scholarship, Columbia University His book on the workings of science for a general audience called Ignorance, How it drives Science was released by Oxford University Press this Spring