Transported to ecstasy

Transported to ecstasy

The pharmaceutical industry relies on the discovery of new, or de-orphaning of recognized, targets. Tremendous effort has been directed at the de-orphaning of GPCRs since they are the targets for numerous therapeutic agents and there are a large number still needing to have native agonists identified.  The various techniques to identify GPCR agonists are still not easy or general, but they are making inroads into a number of novel targets.  Ion channels
are also a rich source of pharmaceuticals.  Huge strides have been made to increase the thruput of ion channel
screening.  However, the speed and efficiency are very much behind that of GPCR’s and enzymes.

Another source of pharmaceutical agents are transporters.  SSRI’s, SNRI’s, and mixed amine uptake inhibitors for major depression are one very strong example.  Dopamine transporter inhibitors – amphetamine, methylphenidate, cocaine – constitute another.  And now that we recognize transporters on numerous membranes – synaptic vesicles, mitochondria, etc. – the scope of their potential uses as pharmaceutical agents becomes very diverse.  However, as yet there are no good technologies to de-orphan transporters.  This is extremely unfortunate since measuring transport activity –
tagged substrates – can be accomplished in a high-throughput manner, equivalent to GPCR’s and enzymes.

Does this lack of techniques belie some special problems with transporters or just the lack of strong efforts?                           I feel it is primarily the latter while acknowledging that much exploratory work must still be done.  It is unreasonable to tag (³H-labelled for example) thousands of different compounds to apply to a concentrated group of transporters.  And, obtaining a rich source of transporters in closed-off membranes (synaptosomes, vesicles, black lipid membranes) also has its difficulties.  Finally, transport requires energy, in the form of ATP hydrolysis, in order to run.  That’s a pretty big list
of problems to be solved, but, I believe the end result will be much greater than the effort expended.

Many transporters contain cotransport for ions, in particular chloride.  Although this cotransport may be small per transporter, it is likely that it could be detected from a rich source of transport activity.  And, I hope and believe, that further study of transporters will provide evidence for additional cotransporters.  Perhaps even ATP hydrolysis itself could
provide a measure of transport activity.  Detection of coexisting activities will likely require rich sources of transporters.  While one can imagine single transporter recordings, it is more difficult to visualize this being high throughput.  

Rich sources will likely mean recombinantly expressing transporters.  This is highly feasible.  The real problems are transporter orientation and energy.  If transporters are randomly oriented in membranes, then overall transport will be zero.  However, application of putative substrates to one side of a membrane should initially produce transport primarily in one direction.  And that interval of one-sided transport may be extendable if the concentration of substrate on the
initial side is kept much higher, for example, by dilution, than on the second side.  Other means, directing the
orientation of membrane insertion or deactivation of transporters from one face, may also be discovered.  Similar
issues will revolve around providing energy to power transport, but I believe these can also be dealt with.

In summary, I believe that the ability to efficiently de-orphan transporters should be a major goal for neurobiology because several of our most powerful drugs affect transport.  While, the road to making this a reality will be arduous,         I believe the end result will be a spectacular opening up of new avenues for discovering novel therapeutics.