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Press Release
The Effects of Ecstasy - It
Takes Two to Tango in the Cell
Amphetamine derivatives like the life style drug Ecstasy cause the release
of neurotransmitters through an ingenious interplay of cellular components:
an enzyme causes two transport proteins of the same type to work in opposite
directions. These new findings are in contrast to previous assumptions
that individual transport proteins alone were responsible for the release
of neurotransmitters by such drugs. The published results of a group at
the Medical University Vienna were obtained with support of the Austrian
Science Fund (FWF). They provide important basic insights into the mode
of action of certain neurotransmitters and drugs.
Ecstasy, Ice and Speed are variations of amphetamines that were originally
developed as appetite suppressants. They are legally banned on account
of their potential to cause addiction and schizophrenic symptoms. From
the beginning of the 90s, however, they came to be used as life style
drugs. Among other things, their effect is based on the similarity of
their chemical structure to that of messengers of the human nervous system.
Paradoxical Effect
These messengers - referred to as neurotransmitters - are transported
by cellular proteins, which extend across the cell membrane. As a rule
those proteins transport the messengers back into the cell in order to
terminate the signal transmission between nerve cells. In case of the
proteins that are responsible for the transport of serotonin (SERT - Serotonin
Transporter), amphetamines engage in the biological transport process
in an interesting way. Project directors Dr. Harald Sitte and Dr. Michael
Freissmuth of the Institute of Pharmacology, Medical University Vienna,
about this: "On account of their similar structure, amphetamines
compete with neurotransmitters for a place on the transport protein. Paradoxically,
it is not this competition, however, that is responsible for the effect
of the amphetamines, but another hitherto little understood phenomenon
- the amphetamines cause the release of natural neurotransmitters and
thus a reversal of the transport direction." For the explanation
of this phenomenon, Dr. Sitte and Dr. Freissmuth together with their colleagues
recently published an attractive model that was well received by the scientific
community.
Transporter Tango
The central aspect of the model is the cooperation of two serotonin transporters
that exist bound to each other. Notwithstanding the similarity of the
proteins, as illustrated in the model, the transporters operate in opposite
directions. The transport reversal is induced by the cellular enzyme protein
kinase C.
The model assumes that in low concentration of amphetamines only one
of the two serotonin transporters is passing amphetamines into the cell.
This process requires a structural alteration of the protein. Initially,
the other transporter remains inactive and thereby retains its original
structure. Consequently, this allows the protein kinase C found in the
cell to gain access to an important activation point.
The amphetamines play a key role in this activation. Dr. Sitte explains:
"To enable the protein kinase C to act at the activation point of
the second serotonin transporter, the enzyme itself must first be activated.
The amphetamine taken up into the cell does exactly that. In a kind of
chain reaction, the now activated protein kinase C activates the hitherto
inactive serotonin transporter. However, the transporter that has originally
transported the amphetamine into the cell cannot offer any access to the
activation point due to its structural change, and thus cannot transport
any serotonin outwards. The effect of the amphetamines is thus quasi dependent
on a pas de deux of two proteins."
This internationally acknowledged model is in sharp contrast to the previous
perceptions that one and the same transport protein transports amphetamines
(into the cell) as well as neurotransmitters (from the cell). The model
of the Viennese group now offers new starting points - e.g. the regulation
of protein kinase C - for optimised therapies of mental disturbances such
as depression or states of anxiety. Therefore, this FWF-supported project
is an excellent example of translational research - to find new opportunities
for applied research by searching for the explanation of fundamental phenomena.
Original publication
Seidel et al., Amphetamines take two to tango: an oligomer-based counter-transport
model of neurotransmitter transport explores the amphetamine action. Mol
Pharmacol 67:140-1512, 2005
Scientific Contact
Dr. Harald H. Sitte
Institute of Pharmacology
Medical University Vienna
Währinger Straße 13
A 1090 Vienna, Austria
M +43 / 664 / 568 41 45
E harald.sitte@meduniwien.ac.at
Austrian Science Fund (FWF)
Mag. Stefan Bernhardt
Issued by
PR&D - Public Relations for Research & Development
Campus Vienna Biocenter 2
A 1030 Vienna
T +43 / 1 / 505 70 44
E contact@prd.at
Vienna, February 21, 2005
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