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G protein-coupled receptors (GPCRs) are promising drug treatment targets.
Almost one third of the drugs approved by the US Food and Drug Administration can affect this family of proteins.
GPCR is expressed in most body tissues and participates in cell communication.
Serotonin 2A receptor (5-HT2AR) is a target of classic hallucinogens and atypical antipsychotics.
Classical psychotropic drugs such as clozapine and diethylamine lysergic acid have been developed based on this target.
5-HT2AR ligands are coupled to a variety of signal transduction pathways through 5-HT2A monomers and heterodimers, resulting in different transcriptome profiles and behavioral characteristics.
In 2018, Associate Professor Lin Tian from the Department of Neuroscience at the University of California developed dLight1, a genetically encoded fluorescent probe of dopamine that can optically record dopamine dynamics in mice with high spatiotemporal resolution under free movement.
The research team is mainly dedicated to the development of genetically encoded imaging probes for use in nervous system research.
On April 28, 2021, Lin Tian’s research team developed a 5-HT2AR ligand fluorescent receptor psychLight2 with millisecond time resolution on the basis of dLight1 in Cell magazine, and discovered a class of non-psychotic, potent antidepressant effects Compound AAZ-A-154.
The researchers replaced the third intracellular loop (IL3) of 5-HT2AR with green fluorescent protein (cpGFP), and added the endoplasmic reticulum membrane output sequence to enhance its ability to locate on the membrane, and developed a report 5-HT2AR The ligand's fluorescent receptor psychLight2.
When activated by serotonin, the receptor expresses fluorescence of corresponding intensity according to the degree of activation.
psychLight2 can detect changes in the concentration of serotonin.
They infected AAV9-hSynapsin1-psychLight2 into cortical neurons cultured in vitro.
After incubating with 5-HT, they can significantly enhance the fluorescence of psychLight2.
In addition, the above-mentioned virus is injected into the nucleus of the stria terminalis to promote the release of 5-HT through electrical stimulation.
Under a two-photon microscope, it can be observed that the fluorescence of psychLight2 changes as the concentration of 5-HT changes.
Optical fiber recording system detects the fluorescence of psychLight2.
In order to further verify the utility of psychLight2, the researchers injected AAV9-hSynapsin1-psychLight2 into the stria terminalis bed nucleus, raphe dorsal nucleus, basolateral amygdala and orbitofrontal cortex, which can be achieved by the optical fiber recording system.
The changes of 5-HT concentration were observed in vivo.
In the fear training experiment, the fluorescence of psychLight2 in the dorsal raphe nucleus increased significantly before the start of the plantar electric shock, and then rapidly decreased.
In the dorsal raphe nucleus, basolateral amygdala and orbitofrontal cortex, only a sharp decrease in the fluorescence intensity of psychLight2 was observed.
These results indicate that psychLight2 can detect changes in endogenous 5-HT concentration in a free state.
The researchers then injected the exogenous agonist 5-MeO-DMT (having hallucinogenic effect) of 5-HT2AR ligand into the intraperitoneal cavity and found an increase in the fluorescence of psychLight2 within 1 minute.
The fluorescence intensity of psychLight2 decreased after injection of the 5-HT2AR ligand antagonist.
They developed a mid-throughput drug screening technology based on psychLight2 to screen compounds (compounds with hallucinogenic and non- hallucinogenic effects), and found that the non- hallucinogenic 5-HT2AR ligand does not activate psychLight2 in the agonist mode, but does not activate psychLight2 in the agonist mode.
Reduce the fluorescence of psychLight2 in antagonist mode.
Ligand compounds that do not bind to 5-HT2AR can neither enhance nor reduce the fluorescence intensity of psychLight2.
This indicates that psychLight2 can distinguish between hallucinogenic and non- hallucinogenic 5-HT2AR ligand compounds.
The potent antidepressant effect of compound AAZ-A-154 Through the above-mentioned drug screening technology, it is found that compound AAZ-A-154 has a non-psychedelic effect, but can reduce the fluorescence of psychLight2 in an antagonist mode.
AAZ-A-154 can significantly reduce the immobility time in forced swimming and relieve the anhedonia symptoms in depression model mice, indicating that AAZ-A-154 has the potential for antidepressant effects.
In general, this article develops a fluorescent probe psychLight2 for 5-HT2AR ligand, which can function under the agonist action of endogenous or exogenous 5-HT2AR ligand.
Unlike other serotonin fluorescent probes, psychLight2 can detect the hallucinogenic effects of hallucinogens.
Surprisingly, AAZ-A-154, a potent antidepressant compound, was identified by psychLight2.
[References] 1.
https://doi.
org/10.
1016/j.
cell.
2021.
03.
043S (2021) The pictures in the article are all from the references
G protein-coupled receptors (GPCRs) are promising drug treatment targets.
Almost one third of the drugs approved by the US Food and Drug Administration can affect this family of proteins.
GPCR is expressed in most body tissues and participates in cell communication.
Serotonin 2A receptor (5-HT2AR) is a target of classic hallucinogens and atypical antipsychotics.
Classical psychotropic drugs such as clozapine and diethylamine lysergic acid have been developed based on this target.
5-HT2AR ligands are coupled to a variety of signal transduction pathways through 5-HT2A monomers and heterodimers, resulting in different transcriptome profiles and behavioral characteristics.
In 2018, Associate Professor Lin Tian from the Department of Neuroscience at the University of California developed dLight1, a genetically encoded fluorescent probe of dopamine that can optically record dopamine dynamics in mice with high spatiotemporal resolution under free movement.
The research team is mainly dedicated to the development of genetically encoded imaging probes for use in nervous system research.
On April 28, 2021, Lin Tian’s research team developed a 5-HT2AR ligand fluorescent receptor psychLight2 with millisecond time resolution on the basis of dLight1 in Cell magazine, and discovered a class of non-psychotic, potent antidepressant effects Compound AAZ-A-154.
The researchers replaced the third intracellular loop (IL3) of 5-HT2AR with green fluorescent protein (cpGFP), and added the endoplasmic reticulum membrane output sequence to enhance its ability to locate on the membrane, and developed a report 5-HT2AR The ligand's fluorescent receptor psychLight2.
When activated by serotonin, the receptor expresses fluorescence of corresponding intensity according to the degree of activation.
psychLight2 can detect changes in the concentration of serotonin.
They infected AAV9-hSynapsin1-psychLight2 into cortical neurons cultured in vitro.
After incubating with 5-HT, they can significantly enhance the fluorescence of psychLight2.
In addition, the above-mentioned virus is injected into the nucleus of the stria terminalis to promote the release of 5-HT through electrical stimulation.
Under a two-photon microscope, it can be observed that the fluorescence of psychLight2 changes as the concentration of 5-HT changes.
Optical fiber recording system detects the fluorescence of psychLight2.
In order to further verify the utility of psychLight2, the researchers injected AAV9-hSynapsin1-psychLight2 into the stria terminalis bed nucleus, raphe dorsal nucleus, basolateral amygdala and orbitofrontal cortex, which can be achieved by the optical fiber recording system.
The changes of 5-HT concentration were observed in vivo.
In the fear training experiment, the fluorescence of psychLight2 in the dorsal raphe nucleus increased significantly before the start of the plantar electric shock, and then rapidly decreased.
In the dorsal raphe nucleus, basolateral amygdala and orbitofrontal cortex, only a sharp decrease in the fluorescence intensity of psychLight2 was observed.
These results indicate that psychLight2 can detect changes in endogenous 5-HT concentration in a free state.
The researchers then injected the exogenous agonist 5-MeO-DMT (having hallucinogenic effect) of 5-HT2AR ligand into the intraperitoneal cavity and found an increase in the fluorescence of psychLight2 within 1 minute.
The fluorescence intensity of psychLight2 decreased after injection of the 5-HT2AR ligand antagonist.
They developed a mid-throughput drug screening technology based on psychLight2 to screen compounds (compounds with hallucinogenic and non- hallucinogenic effects), and found that the non- hallucinogenic 5-HT2AR ligand does not activate psychLight2 in the agonist mode, but does not activate psychLight2 in the agonist mode.
Reduce the fluorescence of psychLight2 in antagonist mode.
Ligand compounds that do not bind to 5-HT2AR can neither enhance nor reduce the fluorescence intensity of psychLight2.
This indicates that psychLight2 can distinguish between hallucinogenic and non- hallucinogenic 5-HT2AR ligand compounds.
The potent antidepressant effect of compound AAZ-A-154 Through the above-mentioned drug screening technology, it is found that compound AAZ-A-154 has a non-psychedelic effect, but can reduce the fluorescence of psychLight2 in an antagonist mode.
AAZ-A-154 can significantly reduce the immobility time in forced swimming and relieve the anhedonia symptoms in depression model mice, indicating that AAZ-A-154 has the potential for antidepressant effects.
In general, this article develops a fluorescent probe psychLight2 for 5-HT2AR ligand, which can function under the agonist action of endogenous or exogenous 5-HT2AR ligand.
Unlike other serotonin fluorescent probes, psychLight2 can detect the hallucinogenic effects of hallucinogens.
Surprisingly, AAZ-A-154, a potent antidepressant compound, was identified by psychLight2.
[References] 1.
https://doi.
org/10.
1016/j.
cell.
2021.
03.
043S (2021) The pictures in the article are all from the references
