When a rabbit, snuffling its way through the woods orfields, picks up the scent of a snake, what does it do?Chances are, the small animal will veer its head back andforth, sniffing first to the left, then to the right, trying tolocate the source of that ominous odor.

It's in the rabbit's best interest to know _ and quickly _where the dangerous reptile is lurking. The alarmedrodent has to be able to detect not just the odor's presencebut its change _ on which side of the trail the smell isstronger.

This means resetting its olfactory chemoreceptor signalfast and frequently. Just how fast is measured inmilliseconds.

A snake broadcasts its don't-tread-on-me warning in theform of odoriferous molecules. These waft through the airto the rabbit's nostrils. Inhaled into its nose, theunmistakable chemical message binds to odor receptorson the olfactory epithelial cells far back in the nasalcavity.

Olfactory sensory neurons then pass the word on to thebrain's olfactory bulbs. These are a pair of pod-likeprotuberances at the ends of long neural tracts in the veryforemost part of the brain. "This is the area," saidmolecular pharmacologist Joseph Beavo, "that gathersinformation from the nose, processes it, and sends it on tothe back part of the brain for smell recognition."

Recalling the rabbit's predicament, he pointed out that"The sensing of an odorant by an animal must be a rapidbut transient process, requiring an instant response andalso a speedy termination of the signal."

In Beavo's laboratory at the University of Washington,Seattle, rats take from 50 to 100 milliseconds to registeran odor; 200 ms to switch it off.

Beavo told BioWorld Today that "most mammals have athousand or more different genes devoted just to olfactoryreceptors, whereas we humans have only four devoted todifferent kinds of options for vision." Humans have some26 million smell receptors on every square inch of theirolfactory epithelium; rabbits, 100 million.

These dichotomies, Beavo suggested, point up theevolutionary importance that nature accords to the senseof smell. Bloodhounds in hot pursuit, he noted, "also veertheir heads to right and left, then make a decision whetherthey want to go this way or that. It's the same idea as therat."

What honchos that split-second on-off transient odorperception is the subject of a paper by Beavo in thecurrent Proceedings of the National Academy ofSciences, dated Oct. 10, 1995. Its title: "Molecularcloning and characterization of a calmodulin-dependentphosphodiesterase [PDE] enriched in olfactory sensoryneurons."

Calmodulin, Beavo explained, "is a small acidic proteinthat binds calcium, and thereby regulates a lot of differentproteins in the body, including this particular PDE."

Two scientists from Icos Corp., of Bothell, Wash., areamong Beavo's co-authors.

"They are very interested in looking at PDEs in humantissues," Beavo observed. "So we initially provided themwith cDNA clones that were at that point bovine. Theyused those to pull out several partial clones to cAMPPDEs, one of which seemed to be novel, with a highaffinity for cAMP."

He continued: "That made us think about data we hadthat there was a high affinity of cam-dependent PDEpresent in olfactory stuff. So we did similar screeningwith polymerase chain reaction in the olfactory, andpulled out the clone that way. The initial observation,"Beavo observed, "was theirs, at Icos. All of the work inthe rat olfactory epithelium was done here."

Phosphodiesterases Rate High On Biotech Charts

The upshot of their joint research, he went on, "theconceptual new thing _ all knowledge beingincremental, of course _ was finding that activation ofthis PDE enzyme is part of the ultra-rapid turn-offmechanism for the initiation of the odorant signal."

On this score, Beavo observed that "there's a hugeinterest in the biotechnology field right now in thephosphodiesterases in general. Because it turns out thatthere are at least seven different genes in several differentgene families, and multiple splice variants in each gene.So there are at least 30 or 40 or 50 of them."

If such is the case, he pointed out, "and you find one, forexample, that's only in vascular smooth muscle, it mightbe a good treatment for hypertension." Similar processes,Beavo suggested, "go on in the kidney or liver orplatelets, or so forth.

"In this olfactory case _ who knows? _ it might havesomething to do with the perfume industry." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.