title: Integrin β3 Haploinsufficiency Modulates Serotonin Transport and Antidepressant-Sensitive Behavior in Mice.
abstract: Converging lines of evidence have identified genetic interactions between the serotonin transporter (SERT) gene and ITGB3, which encodes the β3 subunit that forms the αIIbβ3 and αvβ3 integrin receptor complexes. Here we examine the consequences of haploinsufficiency in the mouse integrin β3 subunit gene (Itgb3) on SERT function and selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) effectiveness in vivo. Biochemical fractionation studies and immunofluorescent staining of murine brain slices reveal that αvβ3 receptors and SERTs are enriched in presynaptic membranes from several brain regions and that αvβ3 colocalizes with a subpopulation of SERT-containing synapses in raphe nuclei. Notably, we establish that loss of a single allele of Itgb3 in murine neurons is sufficient to decrease 5-HT uptake by SERT in midbrain synaptosomes. Pharmacological assays to elucidate the αvβ3-mediated mechanism of reduced SERT function indicate that decreased integrin β3 subunit expression scales down the population size of active SERT molecules and, as a consequence, lowers the effective dose of SSRIs. These data are consistent with the existence of a subpopulation of SERTs that are tightly modulated by integrin αvβ3 and significantly contribute to global SERT function at 5-HT synapses in the midbrain. Importantly, our screen of a normal human population for single nucleotide polymorphisms in human ITGB3 identified a variant associated with reductions in integrin β3 expression levels that parallel our mouse findings. Thus, polymorphisms in human ITGB3 may contribute to the differential responsiveness of select patients to SSRIs.
authors: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Matthew
authors: M
authors: Mazalouskas
authors: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Tammy
authors: T
authors: Jessen
authors: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Seth
authors: S
authors: Varney
authors: 1] Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA [2] Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: James S
authors: JS
authors: Sutcliffe
authors: Department of Psychiatry, Columbia University, New York City, NY, USA.
authors: Jeremy
authors: J
authors: Veenstra-VanderWeele
authors: Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
authors: Edwin H
authors: EH
authors: Cook
authors: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Ana M D
authors: AM
authors: Carneiro
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007223:Infant; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D011903:Raphe Nuclei / Q000166:cytology; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D039661:Integrin beta3; D010751:Phosphopyruvate Hydratase; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors