Alexander Skochko Chris Gilbertson Olfactory Signaling Alexander Skochko Chris Gilbertson

Smell: Who Cares? Reveals Important Features of one’s surroundings Is it poisonous here? Have things died here? Is this food? The absence of the sense of smell is called “Anosmia.” An overly acute sense of smell is known as ‘hypernosmia.’ If you or somebody you know is a hypernosmiac please contact NASA, as their hypernosmiac is getting old – and the job is essential to long missions.

Signaling Pathway for Olfaction A volatile molecule from outside of the body, called an odorant, binds to either: A protein that transfers the odorant to the receptor. Directly to the receptor.

Signaling Pathway for Olfaction The odorant’s ligation with the receptor activates the receptor site, which catalyzes the replacement of GDP on the alpha subunit of a G protein with GTP.

Specificity The enzymatic receptors activated by the binding of odorant molecules have low specificity for the odorants. This allows increased diversity of smells that can activate the receptor neurons in the nose. When two substances smell similar to each other, it is likely that the molecules responsible are similar in nature to each other.

Specificity Continued Since each receptor has the ability to signal for multiple kinds of odorant, olfaction is a burgeoning field of research. There have not been many odorant-receptor ligands identified in the literature.1 Identifying odorant-receptor ligands would not provide much insight into the process of olfaction, as the rest of the process would be the same as other ligands. The receptor changes shape in response to the ligation, and the change in shape results in the activation of the catalytic character of the receptor.

Signaling Pathway for Olfaction 3. The GTP binding now causes the alpha subunit to disassociate from the rest of the G protein, and to subsequently associate with adenylyl cyclase.

Signaling Pathway for Olfaction 4. The G protein binding with adenylyl cyclase activates the enzyme, catalyzing the production of cyclic adenosine monophosphate.

Signaling Pathway for Olfaction 5. The cAMP increase causes calcium ion channels to open, raising the concentration of Ca2+ in the olfactory cell

Signaling Pathway for Olfaction 6.The increased calcium ion concentration causes another gated ion channel to open, this time allowing the release of chloride from the cell. a. The net intake of calcium ions and output of chloride ions causes an increased membrane potential in the receptor cell. If the potential reaches a certain magnitude, the neuron on which the charge is building will send a signal to the brain. This signal is part of what is perceived as a smell.

Signal Integration in Olfaction There is no known route by which olfactory recognition enzymes are deactivated by another olfactory recognition enzyme. Smells are recognized as a variety of signals.2,3 Some odorants have high affinity for some of the Golf receptors, and low affinity for other Golf sites. The combination of signals from high affinity and low affinity sites is what is recognized by the brain as a particular scent. This reliance upon similarity between recognized odorants can have negative results. For examples: cyanide smells of almonds, and phosgene gas smells of liquorish – but one should not inhale either.

Inactivation of Signaling Pathway for Olfaction Phosphodiesterases convert the cyclic adenosine monophosphate back to AMP, shutting down the calcium ion channels. The G protein converts the GTP back to GDP by hydrolysis, causing association of the alpha subunit with the rest of the protein. The receptor protein is then phosphorylated by a kinase, causing temporary inactivation, or ‘Nose Blindness.’

References 1. Bush, C. , Jones, S. , Lyle, A. , Minneman, K. , Ressler, K. , et al. (2007). Specificity of olfactory receptor interactions with other g protein-coupled receptors. Journal of Biological Chemistry, 282(26), 19042-19051. 2. Bettina Malnic, Junzo Hirono, Takaaki Sato, Linda B Buck, Combinatorial Receptor Codes for Odors, Cell, Volume 96, Issue 5, 5 March 1999, Pages 713-723, ISSN 0092-8674, http://dx.doi.org/10.1016/S0092- 8674(00)80581-4. (http://www.sciencedirect.com/science/article/pii/S0092867400805814) 3. Rokni, Dan, Vivian Hemmelder, Vikrant Kapoor, and Venkatesh N Murthy. "An Olfactory Cocktail Party: Figure-ground Segregation of Odorants in Rodents." Nature Neuroscience, 17.9 (2014): 1225-1232. doi: 10.1038/nn.3775 4. Nelson, David. Lehninger Principles of Biochemistry. 5th ed. New York, NY: Sara Tenny, 2008. Page 466.