Treating addiction: Cryo-EM technology enables the 'impossible'

Treating addiction: Cryo-EM technology enables the 'impossible'
Mechanisms of transport and action of ibogaine. Cartoon depicting conformational differences between outward-open, occluded and inward-open conformations. Ibogaine inhibits SERT either by binding to the outward-open conformation followed by stabilization of the occluded or inward-open conformations, or by directly binding to the inward-open conformation. The scaffold domain is shown in grey and TM2, TM7, TM8, TM10 and TM12 are shown in light blue. TM1, TM5 and TM6 are highlighted in orange, green and red. TM4 and TM9 are omitted for clarity. Sodium and chloride ions are shown as red and green spheres, respectively. Credit: Nature (2019). DOI: 10.1038/s41586-019-1135-1

Scientists used a compound found in a shrub native to Africa to reveal the three major shapes of the serotonin transporter, a protein in the brain linked to anxiety and depression.

Using cryo-electron microscopy, the scientists examined the protein binding to ibogaine, an alkaloid that alters brain function and occurs naturally in the shrub iboga. Using ibogaine, researchers reveal the structure of the serotonin transporter in its outward-open, closed and inward-open shapes.

The discovery published today in the journal Nature.

"It means we can target different states of the transporter to modulate its activity," said senior author Eric Gouaux, Ph.D., senior scientist at the OHSU Vollum Institute in Portland, Oregon, and an investigator with the Howard Hughes Medical Institute. "It opens up new thinking of how you might come up with novel molecules to bind to the transporter."

In describing the mechanism of how the protein works with ibogaine, co-authors said they expect the finding may open the door to developing medications that stop addiction without the hallucinogenic and other dangerous properties of ibogaine.

"There's a real need to develop molecules that have these anti-addictive properties," said co-lead author Jonathan Coleman, Ph.D., a researcher in the OHSU Vollum Institute.

In 2016, Gouaux led a team that first revealed the structure of the serotonin transporter, which provided new insight about how the antidepressants citalopram and paroxetine, two of the most widely prescribed , or SSRIs, interact with and inhibit the transport of serotonin.

Influencing virtually all human behaviors, serotonin regulates the activity of the central nervous system as well as processes throughout the body, from cardiovascular function to digestion, body temperature, endocrinology and reproduction. The serotonin transporter acts as a molecular pump for , recycling the neurotransmitter following neuronal signaling. Serotonin shapes neurological processes including sleep, mood, cognition, pain, hunger and aggression.

The new study extends that groundbreaking work by showing the transporter's major conformations, or shapes. The National Institute for Drug Abuse of the National Institutes of Health provided the researchers with ibogaine, which is a Schedule 1 controlled substance that's tightly regulated under U.S. law.

"Most antidepressant drugs bind to the outward-open conformation, and our study shows ibogaine can bind to the inward state," said co-lead author Dongxue Yang, Ph.D., a researcher in Gouaux's lab.

"It provides many more avenues to design with anti-addictive properties," Coleman added.

Cryo-EM enables scientists to visualize molecules in near-atomic detail, however previous work has focused on relatively large proteins. This is one of the smallest molecules to be so clearly revealed through cryo-EM.

"That's a huge development for biomedical science," Gouaux said. "Five years ago, people would have said this was impossible."

Explore further

Researchers visualize brain's serotonin pump, provide blueprint for new, more effective SSRIs

More information: Serotonin transporter–ibogaine complexes illuminate mechanisms of inhibition and transport , Nature (2019). DOI: 10.1038/s41586-019-1135-1 ,
Journal information: Nature

Citation: Treating addiction: Cryo-EM technology enables the 'impossible' (2019, April 24) retrieved 18 July 2019 from
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Apr 25, 2019
Humans are a very unnatural animal. Domestication has given us weak backs, overactive immune systems, large and fragile brains, chronic infection from the other domesticated animals we live in close proximity to.

Our tech has flooded our environments with toxins and contageons. Our culture requires sedentarism and repetitive, mind-numbing work. Our diets resemble little the ones we evolved to digest. We live far longer than we used to, and aging bodies accrue damage and decrepitude that constantly plagues us.

So no doubt we live in a constant state of pain both immediate and subliminal. And when we get an injury and are given medication that leaves us relatively pain-free for perhaps the first time in our lives, and then the medication ends and all that pain returns, of course we want to get back that feeling of normalcy as quickly as possible.

Apr 25, 2019
The domesticated human animal is an artificial construct. We suffer from it physically and emotionally every single day of our lives. We constantly try to self-medicate with the common substances we ingest. We seek out entertainment and physical indulgences such as nonprocreative sex and overeating to distract us from our unremittant pain and mental dysfunction.

And instead of seeking to understand this dilemma, researchers would rather deem this desire to feel normal an addiction. And politicians and academies are only too happy to take up yet another unresolvable cause.

MOST people strive to self-medicate, legally or illegally. This means the compulsion is NORMAL given our artificial physiology. The overwhelming majority of people who take opioids for major, chronic pain do so responsibly and have done so for years, sometimes decades. If their meds stop and they seek out illegal alternatives, it may just kill them.

There are no solutions to problems that dont exist.

Apr 25, 2019
Spinal Evolution

This backbone evolved in fish, for fish
evolved for for legged creatures
where the weight like fish is not supported on the spine
these for legged creatures took it upon themselves
stand upright and walk
full weight immediately fell on the spine
which has never evolved to walk on two legs
this is why
dear Spooky Otto, our backbone suffers chronic back pain
nature has stoped evolving our spine
Spooky Otto, nature is reluctant to change an adaptable design pacifically to walk on two legs
in case, Spooky Otto
Needs to turn back into a fish and go back in to the sea

p.s. spooky otto, with you chronic obsession of human ailments and apparent failings are all in your ghostly apparition, because nature does not see these chronic ailments as failings but a successful adaptable design - as was pointed out oh spooky one, it is time for a fresh start, a new approach and to shed this spooky image, a new avatar

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