Scientists May Have Found Long-Pursued Binding Site for Antidepressants

Discovery could lead to better medications for depression, other mental illnesses

September 28, 2007 • Science Update

NIMH-funded scientists have a major new clue as to where the long-pursued binding site for commonly used antidepressants – potentially the site that triggers the medications’ effects – may be on brain cells. The finding could lead to better medications for depression, but also has important implications for other mental illnesses because it addresses a biological flaw that a number of them share.

The flaw involves a molecular mechanism that maintains the balance of key brain chemicals called neurotransmitters.  The mechanism acts as a pump by transporting neurotransmitters into brain cells when needed, a process in which correct amount and timing are essential for parts of the brain to communicate with each other.  However, the pumps are dysfunctional in depression and some other mental illnesses, including autism and obsessive-compulsive disorder.

Medications called tricyclic antidepressants help offset an imbalance in the neurotransmitters serotonin and norepinephrine by shutting the pumps.  This stops the neurotransmitters from flooding back into the brain cells that emit them, making more available to other cells – thus helping to relieve depression.  However, it was not known how the medications shut the pumps at the molecular level.

The new study is the first to pinpoint a molecular mechanism that could provide an explanation.  Results were published by Satinder Singh, PhD, Atsuko Yamashita, PhD, and Eric Gouaux, PhD, in the August 23 issue of Nature.

Rather than looking at the pump for these neurotransmitters, the researchers used a model in their experiments:  a similar pump found in bacteria.  Both are in a family of pumps called sodium-coupled transporters.  The bacterial pump operates virtually identically to the one in brain cells, but changes in its molecular structure are easier to analyze.

Experiments showed that tricyclic antidepressants latch onto the bacterial pump, changing its molecular structure in a way that effectively plugs it.  Could the medications be affecting similar pumps for serotonin and norepinephrine on human brain cells in the same way?  The researchers are cautious about drawing a direct comparison; the two kinds of pumps are related, but somewhat different.

But now that scientists know that  plugging these kinds of pumps is one way to reduce their activity, researchers may be able to develop medications that target them more directly and efficiently.  This could result in more effective antidepressants with fewer side effects.  The findings may also extend to development of medications for other mental illnesses in which pump dysfunction plays a role.

Reference

Singh SK, Yamashita A, & Gouaux E.  Antidepressant binding site in a bacterial homologue of neurotransmitter transporters . Nature, 2007; 448(7156): 952-956.