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Selective Serotonin...
Selective Serotonin Reuptake Inhibitors within Cells : Temporal Resolution in Cytoplasm, Endoplasmic Reticulum, and Membrane
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- Nichols, Aaron L. (författare)
- CALTECH, Div Biol & Biol Engn, Pasadena, CA 91106 USA.
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- Blumenfeld, Zack (författare)
- CALTECH, Div Biol & Biol Engn, Pasadena, CA 91106 USA.;Univ Southern Calif, Keck Sch Med, Los Angeles, CA 90007 USA.
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- Luebbert, Laura (författare)
- CALTECH, Div Biol & Biol Engn, Pasadena, CA 91106 USA.;Leiden Univ, Inst Biol, NL-2333 Leiden, Netherlands.
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- Knox, Hailey J. (författare)
- CALTECH, Div Chem & Chem Engn, Pasadena, CA 91106 USA.
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- Muthusamy, Anand K. (författare)
- CALTECH, Div Chem & Chem Engn, Pasadena, CA 91106 USA.
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- Marvin, Jonathan S. (författare)
- Janelia Res Campus, Howard Hughes Med Inst, Ashburn, VA 20147 USA.
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- Kim, Charlene H. (författare)
- CALTECH, Div Biol & Biol Engn, Pasadena, CA 91106 USA.
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- Grant, Stephen N. (författare)
- CALTECH, Div Chem & Chem Engn, Pasadena, CA 91106 USA.
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- Walton, David P. (författare)
- CALTECH, Div Chem & Chem Engn, Pasadena, CA 91106 USA.
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- Cohen, Bruce N. (författare)
- CALTECH, Div Biol & Biol Engn, Pasadena, CA 91106 USA.
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- Hammar, Rebekkah (författare)
- Uppsala universitet,Institutionen för farmaci,Uppsala Univ, Dept Pharm, SE-75123 Uppsala, Sweden.
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Looger, Loren (författare)
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- Artursson, Per (författare)
- Uppsala Univ, Dept Pharm, SE-75123 Uppsala, Sweden.;Uppsala Univ, Sci Life Lab Drug Discovery & Dev Platform, SE-75123 Uppsala, Sweden.;Uppsala Univ, Uppsala Univ Drug Optimizat & Pharmaceut Profiling, SE-75123 Uppsala, Sweden.
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- Dougherty, Dennis A. (författare)
- CALTECH, Div Chem & Chem Engn, Pasadena, CA 91106 USA.
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- Lester, Henry A. (författare)
- CALTECH, Div Biol & Biol Engn, Pasadena, CA 91106 USA.
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CALTECH, Div Biol & Biol Engn, Pasadena, CA 91106 USA CALTECH, Div Biol & Biol Engn, Pasadena, CA 91106 USA.;Univ Southern Calif, Keck Sch Med, Los Angeles, CA 90007 USA. (creator_code:org_t)
- SOC NEUROSCIENCE, 2023
- 2023
- Engelska.
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Ingår i: Journal of Neuroscience. - : SOC NEUROSCIENCE. - 0270-6474 .- 1529-2401. ; 43:13, s. 2222-2241
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed treatment for individuals experiencing major depres-sive disorder. The therapeutic mechanisms that take place before, during, or after SSRIs bind the serotonin transporter (SERT) are poorly understood, partially because no studies exist on the cellular and subcellular pharmacokinetic properties of SSRIs in living cells. We studied escitalopram and fluoxetine using new intensity-based, drug-sensing fluorescent reporters targeted to the plasma membrane, cytoplasm, or endoplasmic reticulum (ER) of cultured neurons and mammalian cell lines. We also used chemical detection of drug within cells and phospholipid membranes. The drugs attain equilibrium in neuronal cytoplasm and ER at approximately the same concentration as the externally applied solution, with time constants of a few s (escitalopram) or 200-300 s (fluoxetine). Simultaneously, the drugs accumulate within lipid membranes by >18-fold (escitalo-pram) or 180-fold (fluoxetine), and possibly by much larger factors. Both drugs leave cytoplasm, lumen, and membranes just as quickly during washout. We synthesized membrane-impermeant quaternary amine derivatives of the two SSRIs. The qua-ternary derivatives are substantially excluded from membrane, cytoplasm, and ER for .2.4 h. They inhibit SERT transport -associated currents sixfold or 11-fold less potently than the SSRIs (escitalopram or fluoxetine derivative, respectively), provid-ing useful probes for distinguishing compartmentalized SSRI effects. Although our measurements are orders of magnitude faster than the therapeutic lag of SSRIs, these data suggest that SSRI-SERT interactions within organelles or membranes may play roles during either the therapeutic effects or the antidepressant discontinuation syndrome.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- inside-out pharmacology
- biosensor
- escitalopram
- fluoxetine
- iDrugSnFRs
- pharmacokinetics
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Nichols, Aaron L ...
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Blumenfeld, Zack
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Luebbert, Laura
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Knox, Hailey J.
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Muthusamy, Anand ...
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Marvin, Jonathan ...
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visa fler...
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Kim, Charlene H.
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Grant, Stephen N ...
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Walton, David P.
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Cohen, Bruce N.
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Hammar, Rebekkah
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Looger, Loren
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Artursson, Per
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Dougherty, Denni ...
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Lester, Henry A.
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visa färre...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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Journal of Neuro ...
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Uppsala universitet