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.
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.
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.
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
Dr. Harald H. Sitte
Institute of Pharmacology
Medical University Vienna
Währinger Straße 13
A 1090 Vienna, Austria
M +43 / 664 / 568 41 45
Austrian Science Fund (FWF)
Mag. Stefan Bernhardt
PR&D - Public Relations for Research & Development
Campus Vienna Biocenter 2
A 1030 Vienna
T +43 / 1 / 505 70 44
Vienna, February 21, 2005