tein phosphorylation in the regulation of neuro- 
transmitter receptor and ion channel function. His 
group has found that the nicotinic receptor is phos- 
phorylated at seven distinct sites by three different 
protein kinases. Phosphorylation of the nicotinic 
acetylcholine receptor enhances its desensitization 
to its neurotransmitter, acetylcholine. The phos- 
phorylation (and thus the desensitization) of the 
nicotinic receptor by these three protein kinase sys- 
tems is under the control of at least three different 
neurotransmitters, suggesting that one conse- 
quence of the co-release of transmitters is that it 
provides for the regulation of the sensitivity of 
receptors and hence modulates synaptic trans- 
mission. 
Ion channels in plasma membranes determine 
the electrical behavior of such excitable cells as 
muscles and neurons, and in all cells they control 
the entry and egress of small ions. The laboratory 
of Assistant Investigator Gary Yellen, Ph.D. (The 
Johns Hopkins University) is concerned with the 
molecular mechanisms that determine the ion se- 
lectivity and gating control of ion channels. By 
using genetic techniques to discover and manipu- 
late the structure of ion channel proteins, it is pos- 
sible to correlate particular parts of the protein 
with particular functions. The well-characterized 
nicotinic acetylcholine receptor channel is used as 
a starting point. This channel produces electrical 
excitation in nerve and muscle cells. The laboratory 
is employing several approaches to study mutations 
of the structure of this channel and is attempting to 
clone a gene for a closely related but inhibitory 
channel protein. 
Research in the laboratory of Assistant Investiga- 
tor Susan G. Amara, Ph.D. (Yale University) is con- 
cerned with the molecular biology and regulation 
of genes encoding certain neurotransmitter trans- 
porters that have a central role in synaptic trans- 
mission and are the site of action for a wide range 
of clinically important drugs. Most recently the 
group has pursued a molecular characterization of 
the proteins responsible for neurotransmitter 
reuptake and has developed a functional expres- 
sion system for identifying the genes encoding 
these carriers. They also have continued to explore 
the basic mechanisms for regulating both neuronal 
gene transcription and alternative pathways of pre- 
mRNA processing, using a neuropeptide gene fam- 
ily as a model system. 
The research of Associate Investigator Steven A. 
Siegelbaum, Ph.D. (Columbia University) and his 
colleagues is concerned with the modulation of the 
electrical activity of nerve cells by neurotransmit- 
ters. During the past year they have defined the 
molecular mechanism by which a particular neu- 
ropeptide inhibits the activity of a sensory neuron 
in the marine snail Aplysia calif ornica. They have 
shown that a membrane fatty acid, arachidonic 
acid, is metabolized into 12-HPETE (12-hydro- 
peroxyeicosatetraenoic acid), which then acts di- 
rectly to open a potassium channel in the sensory 
neuron membrane, leading to an inhibition of elec- 
trical excitability. This group has also shown that 
arachidonic acid can modulate ion channel activity 
in vertebrate sympathetic neurons. Here arachi- 
donic acid acts to block an excitatory calcium chan- 
nel, leading to an inhibition of neuronal activity. 
Investigator Richard Axel, M.D. (Columbia Uni- 
versity) and his colleagues have been studying the 
molecular basis for the diverse physiologic actions 
of the neurotransmitter serotonin (5HT). By com- 
bining the techniques of molecular biology with 
those of electrophysiology, his laboratory, in collab- 
oration with that of Dr. Thomas M. Jessell (HHMI, 
Columbia University), has isolated and character- 
ized the genes encoding two distinct 5HT recep- 
tors. They have demonstrated that these genes de- 
fine a new family of neurotransmitter receptors that 
share common structural features and activate com- 
mon intracellular signaling systems. In a series of 
gene transfer experiments, they have demonstrated 
that although in neurons the 5HT receptors are in- 
volved in neurotransmission via regulation of ion 
channel function, in fibroblasts the same receptor 
alters the growth properties of cells and when 
overexpressed can lead to malignant transforma- 
tion. Thus the distinct phenotypic consequences of 
receptor activation in fibroblasts and neurons may 
reflect the different ways in which different cell 
types are programmed to respond to the same set 
of signaling events. 
The research of Investigator Thomas M. Jessell, 
Ph.D. (Columbia University) and his colleagues has 
focused on the cellular and molecular mechanisms 
that determine neuronal cell fate and the pattern- 
ing of neuronal connections in the vertebrate spi- 
nal cord. Neuronal differentiation and axon guid- 
ance have been shown to be regulated by a group 
of specialized epithelial cells that occupy the ven- 
tral midline of the spinal cord. This cell group, 
which forms the so-called floor plate, releases a 
retinoic acid-like morphogen that polarizes embry- 
onic tissues. At early stages of neural tube develop- 
ment, the floor plate may therefore play a role in 
the determination of cell identity and differentia- 
Continued 
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