The Role of Second Messengers 
in Ion Channel Regulation 
Steven A. Siegelbaum, Ph.D. — Associate Investigator 
Dr. Siegelbaum is also Associate Professor of Pharmacology in the Center for Neurobiology and Behavior, 
Columbia University College of Physicians and Surgeons. He received his A.B. degree in biochemical 
sciences from Harvard College and his Ph.D. degree in pharmacology from Yale University, studying the 
role of calcium in cardiac electrical activity. He then did postdoctoral research with David Colquhoun at 
University College, London, and with Philippe Ascher at the Ecole Normale Superieure in Paris, where he 
studied the nicotinic acetylcholine receptor ion channel, before joining the faculty of Columbia University. 
He has received the Herbert J. Kayden Award in Biomedical Science of the New York Academy of Sciences. 
THE electrical activity of nerve and muscle 
cells is regulated by the actions of hormones, 
neurotransmitters, and sensory stimuli such as 
light, odors, and pressure. Regulation of neuro- 
nal activity often depends on the production of 
intracellular second messengers — small metabo- 
lites such as cyclic AMP, cyclic GMP, and various 
products of phospholipid metabolism. These sec- 
ond messengers then act to alter the function of 
ion channels, the membrane proteins that govern 
the electrical signaling of cells. Previous research 
in our laboratory focused on the role that regula- 
tion of ion channel function by second messen- 
gers plays in learning and memory. Recently we 
have become interested in the role of second mes- 
sengers in olfactory signal transduction, the sub- 
ject summarized below. 
The second messenger that was first found to 
play a role in regulating electrical activity was 
cyclic AMP. From initial studies by Earl Suther- 
land and his colleagues, a number of hormones 
and neurotransmitters have been shown to act by 
elevating cAMP concentrations in cells. Later 
studies by Edwin Krebs and his colleagues 
showed that most of the effects of cAMP were due 
to the activation of a cAMP-dependent protein ki- 
nase (cAMP-PK), which phosphorylates many 
types of proteins. Over the past several years it 
has become clear that neurotransmitters can alter 
the activity of ion channels by causing the produc- 
tion of cAMP, leading to the activation of cAMP- 
PK, which can then directly phosphorylate ion 
channels. In general, cAMP-dependent actions 
are relatively slow; they require several seconds 
to produce changes in electrical activity because 
of the relatively slow rates of protein phosphory- 
lation and dephosphorylation. Thus phosphory- 
lation-dependent second messenger actions are 
generally not well suited to mediating rapid neu- 
ronal signaling that occurs during fast synaptic 
transmission or sensory processing. 
Role of Second Messengers in Olfactory 
Signal Transduction 
Olfactory signal transduction has provided neu- 
robiologists with an intriguing puzzle on several 
levels. First, how does the olfactory system recog- 
nize and discriminate among thousands of differ- 
ent odors? Are there a limited number of recep- 
tors that each bind many hundreds of odorants, or 
are there hundreds of receptors that are each spe- 
cific for a single or a few different odorants? Sec- 
ond, how does the binding of an odorant to its 
receptor generate an electrical signal in the olfac- 
tory neuron? Third, how does our olfactory sys- 
tem enable us initially to detect odors at very low 
concentrations and yet become insensitive to the 
same stimuli after several minutes? In one sense 
this form of adaptation is the simplest form of 
learning: our olfactory system "learns" to ignore 
a certain stimulus. 
Recently some of the puzzles associated with 
olfaction began to be solved. Linda Buck and 
Richard Axel (HHMI, Columbia University Col- 
lege of Physicians and Surgeons) identified a sur- 
prisingly large gene family that may code for 
hundreds of distinct odorant receptors in rat ol- 
factory neurons, providing for the requisite speci- 
ficity. The discrepancy between the slow time 
course of most cAMP-mediated responses and the 
more rapid olfactory signaling was resolved when 
Tadashi Nakamura and Geoffrey Gold reported an 
ion channel in toad olfactory neurons that was 
directly activated by cAMP. Thus the activation or 
gating of the channel did not depend on the rela- 
tively slow processes of phosphorylation and de- 
phosphorylation, but rather seemed to be due to 
the direct binding of cAMP to the channel. This 
channel was activated equally well by cAMP or 
cGMP. 
Properties of a Cyclic Nucleotide-gated 
Channel 
The first gene for a cyclic nucleotide-gated 
(CNG) channel to be cloned came from photore- 
ceptors, where the channel participates in photo- 
transduction and is selectively activated by 
cGMP. More recently several laboratories have 
cloned the genes for olfactory neuron CNG chan- 
nels from several species. In collaboration with 
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