title: Heteroreceptor Complexes Formed by Dopamine D1, Histamine H3, and N-Methyl-D-Aspartate Glutamate Receptors as Targets to Prevent Neuronal Death in Alzheimer's Disease.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive memory loss and cognitive dysfunction. Anti-AD strategies targeting cell receptors consider them as isolated units. However, many cell surface receptors cooperate and physically contact each other forming complexes having different biochemical properties than individual receptors. We here report the discovery of dopamine D1, histamine H3, and N-methyl-D-aspartate (NMDA) glutamate receptor heteromers in heterologous systems and in rodent brain cortex. Heteromers were detected by co-immunoprecipitation and in situ proximity ligation assays (PLA) in the rat cortex where H3receptor agonists, via negative cross-talk, and H3receptor antagonists, via cross-antagonism, decreased D1receptor agonist signaling determined by ERK1/2 or Akt phosphorylation, and counteracted D1receptor-mediated excitotoxic cell death. Both D1and H3receptor antagonists also counteracted NMDA toxicity suggesting a complex interaction between NMDA receptors and D1-H3receptor heteromer function. Likely due to heteromerization, H3receptors act as allosteric regulator for D1and NMDA receptors. By bioluminescence resonance energy transfer (BRET), we demonstrated that D1or H3receptors form heteromers with NR1A/NR2B NMDA receptor subunits. D1-H3-NMDA receptor complexes were confirmed by BRET combined with fluorescence complementation. The endogenous expression of complexes in mouse cortex was determined by PLA and similar expression was observed in wild-type and APP/PS1 mice. Consistent with allosteric receptor-receptor interactions within the complex, H3receptor antagonists reduced NMDA or D1receptor-mediated excitotoxic cell death in cortical organotypic cultures. Moreover, H3receptor antagonists reverted the toxicity induced by ß1-42-amyloid peptide. Thus, histamine H3receptors in D1-H3-NMDA heteroreceptor complexes arise as promising targets to prevent neurodegeneration.
authors.affiliation: Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.|Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Rodríguez-Ruiz
authors.affiliation: Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.|Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Moreno
authors.affiliation: Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.|Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Moreno-Delgado
authors.affiliation: Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.|Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Navarro
authors.affiliation: Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.|Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Josefa
authors.initials: J
authors.lastname: Mallol
authors.affiliation: Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.|Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cortés
authors.affiliation: Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.|Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Lluís
authors.affiliation: Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.|Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Enric I
authors.initials: EI
authors.lastname: Canela
authors.affiliation: Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.|Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Vicent
authors.initials: V
authors.lastname: Casadó
authors.affiliation: Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain.|Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.|School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McCormick
authors.affiliation: Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain. rfranco@ub.edu.|Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. rfranco@ub.edu.|Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Diagonal 643, Prevosti Building, 08028, Barcelona, Spain. rfranco@ub.edu.
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000628:therapy*; D000818:Animals; D016923:Cell Death; D002540:Cerebral Cortex / Q000473:pathology; D004735:Energy Transfer; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D000066829:Neuroprotection; D010766:Phosphorylation; D055503:Protein Multimerization; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017447:Receptors, Dopamine D1; D018100:Receptors, Histamine H3; D016194:Receptors, N-Methyl-D-Aspartate; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Alzheimers disease; Dementia; G-protein-coupled receptors; Heteroreceptor complexes; Ionotropic receptor; Neurodegeneration; Neuroprotection; Parkinson’s disease; Receptor heteromers; Transgenic animals