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DR^ERSE ROLES OF CYCLIC NUCLEOTIDES IN NEURONAL SIGNALING 
Steven A. Siegelbaum, Ph.D., Associate Investigator 
Cyclic nucleotides play a number of impor- 
tant roles in neuronal signaling. The first well- 
characterized action of cAMP in neurons was as a 
second messenger for certain modulatory transmit- 
ter actions. Here the binding of transmitter to its 
membrane receptor was shown to lead to an eleva- 
tion of cAMP with a resultant activation of the cAMP- 
dependent protein kinase, leading to an increase in 
protein phosphorylation. Phosphorylation of ion 
channels was shown to underlie the modulatory 
changes in neuronal electrical activity. Transmitter 
actions mediated by this cAMP cascade were gener- 
ally characterized by their relatively slow time 
course, lasting many seconds to several minutes. 
Thus it was somewhat surprising when it was shown 
that cyclic nucleotides also mediate more-rapid 
forms of neuronal signaling associated with both vi- 
sual and olfactory sensory signal transduction. Such 
rapid signaling roles for cyclic nucleotides depend 
on the direct activation of cyclic nucleotide-gated 
(CNG) ion channels through the binding of cGMP 
or cAMP to the channel. Over the past several years a 
number of laboratories have cloned related CNG 
channels from photoreceptor and olfactory receptor 
neurons. During the past year, research in Dr. Sie- 
gelbaum's laboratory has focused on the biophysical 
properties of a CNG channel from catfish olfactory 
neurons and the role of this channel in olfactory 
signal transduction. 
The catfish olfactory CNG channel was cloned in 
collaboration with Dr. Richard Axel (HHMI, Colum- 
bia University), and the channel was then expressed 
in Xenopus oocytes. The genes for CNG channels 
from bovine photoreceptors as well as rat, bovine, 
and catfish olfactory neurons are highly homolo- 
gous, with ~70% identity at the amino acid se- 
quence level. As pointed out by Drs. Benjamin 
Kaupp and Shosaku Numa, these channels all con- 
tain a domain near the carboxyl terminus that is ho- 
mologous to the cyclic nucleotide-binding do- 
mains of the cAMP- and cGMP-dependent protein 
kinases. Although gated by cyclic nucleotides, these 
channels show significant homology with the 
voltage-gated channel family and contain a putative 
NEUROSCIENCE 437 
