GLIM, Spring 1996, volume 2

Nevertheless,
it is extremely hard to prove that each neuron only
expresses one receptor type. Although in situ hybridization
never revealed double labeling of any cell for probes with
two different receptor types, it could be because the exper-
imenters used the wrong two probes. The experimenters
only tried using probes for a few of the thousands of differ-
ent receptor types that exist. Perhaps, had they used
probes for different receptors types, they would have
observed double labeling. Just because the researchers
failed to find something, it does not mean that the some-
thing they were looking for does not exist. In addition,
allelic inactivation, as shown by Axel, only provides a
mechanism for how one receptor type might be expressed
on one neuron, but it does not mean that only one recep-
tor type is necessarily expressed on one neuron. While the
one neuron, one receptor type theory has a lot of evidence
to support it, the debate is still far from settled.

Like other G—protein linked receptors, the olfactory
receptors are capable of activating two pathways, the
cAMP mediated pathway and the phosphatidylinositol
inositol bisphosphate pathway. After an odorant mole-
cule binds to the receptor, if the cAMP pathway is
utilized by that ligand, then Goj¢ is activated
(Anholt, 1993). Goj activates an adenylate
cyclase specific to olfactory neurons known
as adenylate cyclase type III, which utilizes
ATP to make cAMP. In order to
explain why the olfactory system
uses a unique G protein and a
unique adenylyl cyclase, some
scientists


















olfactory
system must

be capable
Oo ti







detect-
ing very
weak signals
against potentially
very strong background
noise and thus, the unique G
proteins and adenylate cyclase help
overcome these problems and are espe-
cially good at amplifying very weak signals
(Anholt, 1993). ;
If the cAMP pathway is not utilized, an olfactory
neuron might use the phosphatidylinositol bisphosphate
pathway. No one has found a neuron that generates both
cAMP and inositol trisphosphate in response to oderants,
suggesting that these pathways are mutually exclusive in
olfactory neurons (Breer, 1993A). Although one might
expect that odorant molecules that elicit cAMP all are
structurally related and the molecules that elicit inositol
triphosphate are all structurally related, in fact there is
nothing obvious that molecules that elicit a particular sec-
ond messenger pathway have in common (Breer, 1993A).
For the PIP7 pathway to be utilized, a G protein must be
activated. At this point, it is unknown whether G5 j¢ acti-
vates a phospholipase C or whether a G protein that has
not been discovered is responsible for activating the
enzyme. As in other cells, eventually calcium is released
from the endoplasmic reticulum and a protein kinase C
gets activated. Some have argued that the calcium actual-
ly binds to calmodulin which then activates adenylate
cyclase and thus the PIP7 pathway ultimately generates
the same products as the cAMP pathway (Anholt, 1993).
If both pathways generate cAMP, then why olfactory cells
generate cAMP through a less direct method via the PIP
pathway is unclear. Figure two summarizes these pathways.
There is some evidence that nitric oxide acts a second
messenger in olfactory cells. Nitric oxide is a gas that acti-
vates the enzyme Guanylate cyclase which produces
cGMP from GTP (Vincent & Hope, 1992). Nitric oxide is
thought to act as a second messenger in a number of dif-
ferent systems in the brain (Vincent & Hope, 1992). In
situ hybridization of rat brain using a probe for mRNA of
nitric oxide synthase, the enzyme that catalyzes the forma-
tion of nitric oxide, showed that the greatest amount of
nitric oxide synthase is located in the olfactory bulb and in
the cerebellum (Breer & Shepherd, 1993C). In addition,
other studies have indi-
cated that there is a
rise in CGMP in both
purified olfactory
cilia and olfac-
tory neurons
after exposing
them to oder-
ants (Breer