voltage sensor (S4) membrane-spanning domain 
and a membrane domain (H5 or SS1-SS2) thought to 
form the lining of the pore. 
To test whether the CNG channels show any func- 
tional similarity to the voltage-gated channels, Dr. 
Siegelbaum and his colleagues have used single- 
channel recording to study the properties of the 
cloned CNG channel expressed in Xenopus oo- 
cytes. The channel is activated equally well by cAMP 
and cGMP with a K-y^2 for activation of ~50 pan 
and a Hill coefficient of 1.4, suggesting that the 
binding of two or more cyclic nucleotide molecules 
is required for activation. At the single-channel 
level, increasing concentrations of cyclic nucleo- 
tides lead to an increase in channel open probability 
and open burst duration. The single-channel current 
shows a main open conductance state of ~55 pS, 
with a prominent subconductance state of ~27 pS. 
Entry into this subconductance state depends on the 
binding of protons to an external site on the channel 
and is relieved by large depolarizations. This behav- 
ior is similar to that described by Dr. Peter Hess and 
his colleagues for the subconductance state of 
voltage-gated calcium channels. Patch-clamp stud- 
ies of the catfish CNG channel in native olfactory 
neurons reveal similar properties. However, the na- 
tive channel is 20-fold more sensitive to cyclic nu- 
cleotides of 2-3 mM). Future experiments are 
planned to address this discrepancy. 
Does the S4 region confer significant voltage de- 
pendence to channel gating? Dr. Siegelbaum and his 
colleagues find that the gating of the channel de- 
pends only weakly on membrane voltage, similar to 
the results of others. Channel open probability in- 
creases by a factor of two for a 100-mV depolariza- 
tion. This weak voltage dependence is 10- to 20-fold 
less than the voltage dependence of typical voltage- 
gated channels. Apparently the S4 domain does not 
confer significant voltage dependence. 
In other work, Dr. Siegelbaum and his colleagues 
are focusing on the role of the catfish CNG channel 
in olfactory adaptation. A prominent feature of olfac- 
tory signal transduction is that prolonged exposure 
to an odorant causes a relatively rapid decline (or 
adaptation) in the response of an olfactory neuron 
to that odorant. A rise in intracellular calcium has 
been proposed to be important in olfactory adapta- 
tion, although the mechanism whereby calcium re- 
duces the response to an odorant is not known. Dr. 
Richard Kramer and Dr. Siegelbaum have studied 
the possibility that internal calcium may regulate 
the functioning of the olfactory CNG channel. 
These studies were performed on CNG channels 
in membrane patches obtained from catfish olfac- 
tory neurons. Elevating internal calcium was found 
to have a profound inhibitory effect on the activa- 
tion of these channels by cyclic nucleotides. Cal- 
cium was found to act by shifting the dose-response 
curve for channel activation to higher cyclic nu- 
cleotide concentrations without altering the maxi- 
mal response. Moreover, this effect occurs at physio- 
logical levels of calcium. Half-maximal inhibition 
occurs at ~3 mM Ca^"^. 
How does internal calcium inhibit the activation 
of the CNG channel? A series of pharmacological 
experiments showed that this inhibitory effect does 
not depend on activation of a phosphodiesterase, 
protein kinases, protein phosphatases, or on calmod- 
ulin. However, the inhibitory action of calcium also 
does not appear to result from a direct action of 
calcium on the CNG channel, because the effect 
gradually washes out over 1 5-30 min after a patch is 
excised from an olfactory neuron. Moreover, the 
cloned CNG channel expressed in Xenopus oocytes 
does not exhibit the calcium inhibition. Thus it was 
concluded that calcium acts on an accessory protein 
that is associated with the CNG channel in olfactory 
neuron membranes. 
Thus the olfactory system provides a useful model 
for studying neuronal signal transduction and neuro- 
nal plasticity. Studies on the molecular bases of 
these phenomena should provide insight into many 
of the basic mechanisms controlling nerve cell 
behavior. 
Dr. Siegelbaum is also Associate Professor of 
Pharmacology in the Center for Neurobiology and 
Behavior at Columbia University College of Physi- 
cians and Surgeons. 
Books and Chapters of Books 
Kandel, E.R., and Siegelbaum, S.A. 1991 • Directly 
gated transmission at the nerve-muscle synapse. 
In Principles of Neural Science (Kandel, E.R., 
Schwartz, J.H., and Jessell, T.M., Eds.). New 
York: Elsevier, pp 135-152. 
Kandel, E.R., Siegelbaum, S.A., and Schwartz, 
J.H. 1991 . Synaptic transmission. In Principles of 
Neural Science (Kandel, E.R., Schwartz, J.H., 
and Jessell, T.M., Eds.). New York: Elsevier, pp 
123-134. 
Siegelbaum, S.A., and Koester, J. 1991. Ion chan- 
nels. In Principles of Neural Science (Kandel, 
E.R., Schwartz, J.H., and Jessell, T.M., Eds ). 
New York: Elsevier, pp 66-79. 
Articles 
Goulding, E.H., Ngai, J., Kramer, R.H., Colicos, 
S., Axel, R., Siegelbaum, S.A., and Chess, A. 
438 
