Novel modulation of serotonin receptors

Summary

Principal Investigator: Milt Teitler
Affiliation: Albany Medical College
Country: USA
Abstract: DESCRIPTION (provided by applicant): Novel mechanisms of modulating GPCR function may result in improved therapeutics for treating many diseases including schizophrenia and depression. Studies performed during the previous funding cycle of this grant revealed two unexpected effects of drugs on h5-HT6 and h5-HT7 receptor activity. 1. Two groups of inverse agonists have been discovered: "high affinity/high potency" inverse agonists with potencies that are predicted from their affinities for the receptor, and "high affinity/low potency" inverse agonists with potencies that are far lower than predicted from their binding affinities for the receptor. 2.The second unexpected result is that risperidone (a widely prescribed antipsychotic drug), 9-OH-risperidone (the active metabolite of risperidone), and methiothepin produce a rapid and potent inactivation of the native h5-HT7 receptor (inactivating antagonists). Therefore, this proposal involves two specific aims: 1) determine the mechanism of action of high potency vs. low potency inverse agonists at CAM h5-HT6 and 5-HT7 receptors;and 2) determine the mechanism(s) of action that results in risperidone's rapid and potent inactivation of the native h5-HT7 receptor. Specific aim"1 will be approached in three ways: a) detailed pharmacological analysis of the actions of inverse agonists at the CAM h5-HT6 and h5-HT7 receptors to determine if an allosteric mechanism may be involved;b) monitor the effects of inverse agonists on CAM h5-HT6 and h5- HT7 receptor internalization and beta-arrestin translocation;c) monitor the effects of inverse agonists on CAM h5-HT6 and h5-HT7 receptor associated MARK activity. Specific aim 2 will be approached in three ways: a) determine if inactivating antagonists interact irreversibly with the native h-5HT7 receptor in intact cell preparations;b) monitor the effects of inactivating antagonists on native h5-HT7 receptor internalization and beta-arrestin translocation, and c) monitor the effects of inactivating antagonist treatment on MARK activity in cells expressing native h5-HT7 receptors. The results from these studies may reveal novel mechanisms for modulating the functional state of h5-HT6 and h5-HT7 receptors, which may be applicable to many other GPCR. Dysfunctions of these modulating mechanisms may underly the psychopathology of various mental diseases. These studies may lead to the development of novel therapeutics for brain dysfunctions, including schizophrenia and depression.
Funding Period: ----------------1997 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. ncbi Risperidone irreversibly binds to and inactivates the h5-HT7 serotonin receptor
    Carol Smith
    A 136, Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, USA
    Mol Pharmacol 70:1264-70. 2006
  2. pmc A new approach for studying GPCR dimers: drug-induced inactivation and reactivation to reveal GPCR dimer function in vitro, in primary culture, and in vivo
    Milt Teitler
    Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA
    Pharmacol Ther 133:205-17. 2012
  3. pmc Toward selective drug development for the human 5-hydroxytryptamine 1E receptor: a comparison of 5-hydroxytryptamine 1E and 1F receptor structure-affinity relationships
    Michael T Klein
    Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA
    J Pharmacol Exp Ther 337:860-7. 2011
  4. pmc Antagonist interaction with the human 5-HT(7) receptor mediates the rapid and potent inhibition of non-G-protein-stimulated adenylate cyclase activity: a novel GPCR effect
    M T Klein
    Albany Medical College, Center for Neuropharmacology and Neuroscience, 47 New Scotland Avenue, MC 136, Albany, NY 12208, USA
    Br J Pharmacol 162:1843-54. 2011
  5. pmc Risperidone-induced inactivation and clozapine-induced reactivation of rat cortical astrocyte 5-hydroxytryptamine₇ receptors: evidence for in situ G protein-coupled receptor homodimer protomer cross-talk
    Carol Smith
    Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, USA
    Mol Pharmacol 79:318-25. 2011
  6. pmc Clozapine and other competitive antagonists reactivate risperidone-inactivated h5-HT7 receptors: radioligand binding and functional evidence for GPCR homodimer protomer interactions
    Milt Teitler
    Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA
    Psychopharmacology (Berl) 212:687-97. 2010
  7. pmc Human 5-HT7 receptor-induced inactivation of forskolin-stimulated adenylate cyclase by risperidone, 9-OH-risperidone and other "inactivating antagonists"
    Nicole Toohey
    Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA
    Mol Pharmacol 76:552-9. 2009
  8. pmc Guinea pig hippocampal 5-HT(1E) receptors: a tool for selective drug development
    Michael T Klein
    Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York 12208, USA
    J Neurochem 109:268-74. 2009
  9. pmc Pharmacological analysis of the novel, rapid, and potent inactivation of the human 5-Hydroxytryptamine7 receptor by risperidone, 9-OH-Risperidone, and other inactivating antagonists
    Jessica A Knight
    Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208
    Mol Pharmacol 75:374-80. 2009
  10. pmc Distribution of 5-ht(1E) receptors in the mammalian brain and cerebral vasculature: an immunohistochemical and pharmacological study
    M T Klein
    Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA
    Br J Pharmacol 166:1290-302. 2012

Scientific Experts

  • Milt Teitler
  • Michael T Klein
  • Carol Smith
  • Nicole Toohey
  • M T Klein
  • Jessica A Knight
  • Richard A Glennon
  • Małgorzata Dukat
  • Jessica Knight
  • Katharine Herrick-Davis
  • Joseph Mazurkiewicz
  • Tariq Rahman

Detail Information

Publications10

  1. ncbi Risperidone irreversibly binds to and inactivates the h5-HT7 serotonin receptor
    Carol Smith
    A 136, Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, USA
    Mol Pharmacol 70:1264-70. 2006
    ..At the very least, the possibility that highly prescribed drugs, such as risperidone, are irreversibly antagonizing GPCR function in vivo is noteworthy...
  2. pmc A new approach for studying GPCR dimers: drug-induced inactivation and reactivation to reveal GPCR dimer function in vitro, in primary culture, and in vivo
    Milt Teitler
    Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA
    Pharmacol Ther 133:205-17. 2012
    ..The data obtained using the 5-HT(7) and 5-HT(2A) receptors are strongly supportive of a GPCR homodimer structure, with little evidence of monomer involvement in the function of these receptors...
  3. pmc Toward selective drug development for the human 5-hydroxytryptamine 1E receptor: a comparison of 5-hydroxytryptamine 1E and 1F receptor structure-affinity relationships
    Michael T Klein
    Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA
    J Pharmacol Exp Ther 337:860-7. 2011
    ..The insights generated from this study will inform future drug development and molecular modeling studies for both 5-HT(1E) and 5-HT(1F) receptors...
  4. pmc Antagonist interaction with the human 5-HT(7) receptor mediates the rapid and potent inhibition of non-G-protein-stimulated adenylate cyclase activity: a novel GPCR effect
    M T Klein
    Albany Medical College, Center for Neuropharmacology and Neuroscience, 47 New Scotland Avenue, MC 136, Albany, NY 12208, USA
    Br J Pharmacol 162:1843-54. 2011
    ..Herein, we sought to determine if competitive antagonists also affect forskolin-stimulated activity and if this effect is common among other G(s) -coupled receptors...
  5. pmc Risperidone-induced inactivation and clozapine-induced reactivation of rat cortical astrocyte 5-hydroxytryptamine₇ receptors: evidence for in situ G protein-coupled receptor homodimer protomer cross-talk
    Carol Smith
    Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, USA
    Mol Pharmacol 79:318-25. 2011
    ..The homodimer structure and protomer-protomer cross-talk offer new avenues of research into receptor dysfunction in disease states and the development of novel drugs...
  6. pmc Clozapine and other competitive antagonists reactivate risperidone-inactivated h5-HT7 receptors: radioligand binding and functional evidence for GPCR homodimer protomer interactions
    Milt Teitler
    Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA
    Psychopharmacology (Berl) 212:687-97. 2010
    ..Although risperidone and 9-OH-risperidone ("inactivating antagonists") completely inactivate the receptor, only 50% of the receptors form a pseudo-irreversible complex with these drugs...
  7. pmc Human 5-HT7 receptor-induced inactivation of forskolin-stimulated adenylate cyclase by risperidone, 9-OH-risperidone and other "inactivating antagonists"
    Nicole Toohey
    Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA
    Mol Pharmacol 76:552-9. 2009
    ..These drugs may produce innovative approaches to the development of therapeutic drugs...
  8. pmc Guinea pig hippocampal 5-HT(1E) receptors: a tool for selective drug development
    Michael T Klein
    Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York 12208, USA
    J Neurochem 109:268-74. 2009
    ..Using the guinea pig as an animal model should provide important insights into possible functions of this receptor and the therapeutic potential of selective human 5-HT(1E) drugs...
  9. pmc Pharmacological analysis of the novel, rapid, and potent inactivation of the human 5-Hydroxytryptamine7 receptor by risperidone, 9-OH-Risperidone, and other inactivating antagonists
    Jessica A Knight
    Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208
    Mol Pharmacol 75:374-80. 2009
    ..The rapid, potent inactivation of the receptor-G-protein complex by antagonists implies a constitutive, pre-existing complex between the h5-HT(7) receptor and a G-protein...
  10. pmc Distribution of 5-ht(1E) receptors in the mammalian brain and cerebral vasculature: an immunohistochemical and pharmacological study
    M T Klein
    Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA
    Br J Pharmacol 166:1290-302. 2012
    ..However, neither the function nor the distribution of this receptor has been characterized in the mammalian brain...