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Mystery receptor's binding partner uncovered
12 February 2009
The hallucinogen N,N-dimethyltryptamine, the active ingredient of mind-bending snuffs and sacramental teas used in shamanic rituals in South America and which also occurs naturally in the body, has been unmasked as the binding partner for a widely occurring receptor molecule whose function remains unknown.
For decades scientists have puzzled over the role of the sigma-1 receptor, a protein found in almost all mammalian cells, including the nervous system. A key question that remained elusive was the identity of natural ligands for the protein.
Dimethyltriptamine
N,N-dimethyltriptamine
© Science
Now a team led by Arnold Ruoho of the University of Wisconsin in the US has provided compelling evidence that dimethyltryptamine, or DMT, is one of sigma-1's ligands.
Sigma-1 was known to bind a range of molecules with a common chemical backbone. Ruoho and his team searched for naturally occurring compounds with the key structure. They alighted upon DMT, which has been found in human blood, urine and cerebrospinal fluid, but whose function in the body is not known.
The team showed that in the test tube DMT was able to displace molecules that are known to bind with high affinity to sigma-1. They then compared the effect of DMT on heart muscle cells from mice that possessed sigma-1 with those genetically engineered not to produce the receptor - so-called sigma-1 receptor knock-out mice. Here, the activity of an ion channel was inhibited where sigma-1 was present, but unaffected in its absence. Ion channels are important in cell signalling processes, and the result suggest not only that DMT is interacting with sigma-1, but also that sigma-1 might be an ion-channel regulator.
Sigma-1 pharmacophore
The team analysed known sigma-1 ligands to identify the key structural features
© Science
Finally the team gave DMT to mice with and without the receptor. 'We showed that DMT increased the activity of wild-type mice, but in the knock-out mice there was no response,' says Ruoho.
Intriguingly both sigma-1 receptors and endogenously occurring DMT have been implicated in diseases such as schizophrenia. The new results open the way, says Ruoho, to search for synthetic compounds based on DMT that bind more powerfully to the receptor and observe their effects.
'This is a very important finding and will lead to more interest in the role of DMT and the sigma-1 receptor in mental illness,' says James Stone of the Institute of Psychiatry in London. 'People did not know what the natural ligand of sigma-1 was, and this has led to a lot of blind alleys. So this is really big news.'
Radiochemist Erik Arstad, of University College London, who has worked on sigma-1 receptors, agrees that the finding is significant. 'Given the potent hallucinogenic effects of DMT, its presence in the human body has so far been a mystery. The role of the sigma-1 receptor is also poorly understood, so the suggested link between endogenous DMT levels and modulation of the sigma-1 receptor is intriguing. The findings are likely to spur considerable interest in the sigma-1 receptor, as well as trace amines, particularly in relation to mental illnesses such as schizophrenia.'
Simon Hadlington
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References
D Fontanilla et. al., Science, 2009, 323, 934, DOI: 10.1126/science.1166127
www.rsc.org/chemistrywor.../12020901.asp
12 February 2009
The hallucinogen N,N-dimethyltryptamine, the active ingredient of mind-bending snuffs and sacramental teas used in shamanic rituals in South America and which also occurs naturally in the body, has been unmasked as the binding partner for a widely occurring receptor molecule whose function remains unknown.
For decades scientists have puzzled over the role of the sigma-1 receptor, a protein found in almost all mammalian cells, including the nervous system. A key question that remained elusive was the identity of natural ligands for the protein.
Dimethyltriptamine
N,N-dimethyltriptamine
© Science
Now a team led by Arnold Ruoho of the University of Wisconsin in the US has provided compelling evidence that dimethyltryptamine, or DMT, is one of sigma-1's ligands.
Sigma-1 was known to bind a range of molecules with a common chemical backbone. Ruoho and his team searched for naturally occurring compounds with the key structure. They alighted upon DMT, which has been found in human blood, urine and cerebrospinal fluid, but whose function in the body is not known.
The team showed that in the test tube DMT was able to displace molecules that are known to bind with high affinity to sigma-1. They then compared the effect of DMT on heart muscle cells from mice that possessed sigma-1 with those genetically engineered not to produce the receptor - so-called sigma-1 receptor knock-out mice. Here, the activity of an ion channel was inhibited where sigma-1 was present, but unaffected in its absence. Ion channels are important in cell signalling processes, and the result suggest not only that DMT is interacting with sigma-1, but also that sigma-1 might be an ion-channel regulator.
Sigma-1 pharmacophore
The team analysed known sigma-1 ligands to identify the key structural features
© Science
Finally the team gave DMT to mice with and without the receptor. 'We showed that DMT increased the activity of wild-type mice, but in the knock-out mice there was no response,' says Ruoho.
Intriguingly both sigma-1 receptors and endogenously occurring DMT have been implicated in diseases such as schizophrenia. The new results open the way, says Ruoho, to search for synthetic compounds based on DMT that bind more powerfully to the receptor and observe their effects.
'This is a very important finding and will lead to more interest in the role of DMT and the sigma-1 receptor in mental illness,' says James Stone of the Institute of Psychiatry in London. 'People did not know what the natural ligand of sigma-1 was, and this has led to a lot of blind alleys. So this is really big news.'
Radiochemist Erik Arstad, of University College London, who has worked on sigma-1 receptors, agrees that the finding is significant. 'Given the potent hallucinogenic effects of DMT, its presence in the human body has so far been a mystery. The role of the sigma-1 receptor is also poorly understood, so the suggested link between endogenous DMT levels and modulation of the sigma-1 receptor is intriguing. The findings are likely to spur considerable interest in the sigma-1 receptor, as well as trace amines, particularly in relation to mental illnesses such as schizophrenia.'
Simon Hadlington
Interesting story? Spread the word using the 'tools' menu on the left.
References
D Fontanilla et. al., Science, 2009, 323, 934, DOI: 10.1126/science.1166127
www.rsc.org/chemistrywor.../12020901.asp
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Re: DMT as Reality Thermostat
Fri, June 19, 2009 - 11:43 PM
Trace-amine octopamine has been seen to mostly control neuro-transmissions in insects'
Octopamine is a biogenic amine that is closely related to noradrenaline, and has noradrenergic and dopaminergic effects.
In invertebrates, the biogenic-amine octopamine is an important physiological regulator. It controls and modulates neuronal development, circadian rhythm, locomotion, 'fight or flight' responses, as well as learning and memory. Octopamine mediates its effects by activation of different GTP-binding protein (G protein)-coupled receptor types, which induce either cAMP production or Ca(2+) release.
Here we describe the functional characterization of two genes from Drosophila melanogaster that encode three octopamine receptors. The first gene (Dmoa1) codes for two polypeptides that are generated by alternative splicing.
When heterologously expressed, both receptors cause oscillatory increases of the intracellular Ca(2+) concentration in response to applying nanomolar concentrations of octopamine.
The second gene (Dmoa2) codes for a receptor that specifically activates adenylate cyclase and causes a rise of intracellular cAMP with an EC(50) of approximately 3 x 10(-8) m octopamine.
Tyramine, the precursor of octopamine biosynthesis, activates all three receptors at > or = 100-fold higher concentrations, whereas dopamine and serotonin are non-effective.
Developmental expression of Dmoa genes was assessed by RT-PCR.
Overlapping but not identical expression patterns were observed for the individual transcripts.
The genes characterized in this report encode unique receptors that display signature properties of native octopamine receptors.
Also DMT is intrinsicaly tied to Calcium ion channels'
Why should humans be any different ?
Bliss
Nobuoni +
