Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

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 H3 receptor agonists, via negative cross-talk, and H3 receptor antagonists, via cross-antagonism, decreased D1 receptor agonist signaling determined by ERK1/2 or Akt phosphorylation, and counteracted D1 receptor-mediated excitotoxic cell death. Both D1 and H3 receptor antagonists also counteracted NMDA toxicity suggesting a complex interaction between NMDA receptors and D1-H3 receptor heteromer function. Likely due to heteromerization, H3 receptors act as allosteric regulator for D1 and NMDA receptors. By bioluminescence resonance energy transfer (BRET), we demonstrated that D1 or H3 receptors 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, H3 receptor antagonists reduced NMDA or D1 receptor-mediated excitotoxic cell death in cortical organotypic cultures. Moreover, H3 receptor antagonists reverted the toxicity induced by ß1–42-amyloid peptide. Thus, histamine H3 receptors in D1-H3-NMDA heteroreceptor complexes arise as promising targets to prevent neurodegeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Thathiah A, De Strooper B (2011) The role of G protein-coupled receptors in the pathology of Alzheimer’s disease. Nat Rev Neurosci 12:73–87. doi:10.1038/nrn2977

    Article  CAS  PubMed  Google Scholar 

  2. Borchelt DR, Thinakaran G, Eckman CB et al (1997) Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs. J Neurosci 1762:10090–10101. doi:10.1523/JNEUROSCI.4147-13.2014

    Google Scholar 

  3. Borchelt DR, Thinakaran G, Eckman CB et al (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 17:1005–13

    Article  CAS  PubMed  Google Scholar 

  4. Jürgensen S, Antonio LL, Mussi GEA et al (2011) Activation of D1/D5 dopamine receptors protects neurons from synapse dysfunction induced by amyloid-beta oligomers. J Biol Chem 286:3270–6. doi:10.1074/jbc.M110.177790

    Article  PubMed  Google Scholar 

  5. Cowburn RF, Wiehager B, Trief E et al (1997) Effects of beta-amyloid-(25–35) peptides on radioligand binding to excitatory amino acid receptors and voltage-dependent calcium channels: evidence for a selective affinity for the glutamate and glycine recognition sites of the NMDA receptor. Neurochem Res 22:1437–42

    Article  CAS  PubMed  Google Scholar 

  6. Ferrada C, Moreno E, Casadó V et al (2009) Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors. Br J Pharmacol 157:64–75. doi:10.1111/j.1476-5381.2009.00152.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Moreno E, Vaz SH, Cai N-S et al (2011) Dopamine-galanin receptor heteromers modulate cholinergic neurotransmission in the rat ventral hippocampus. J Neurosci 31:7412–23. doi:10.1523/JNEUROSCI.0191-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hersi AI, Richard JW, Gaudreau P, Quirion R (1995) Local modulation of hippocampal acetylcholine release by dopamine D1 receptors: a combined receptor autoradiography and in vivo dialysis study. J Neurosci 15:7150–7

    CAS  PubMed  Google Scholar 

  9. Seong HJ, Carter AG (2012) D1 receptor modulation of action potential firing in a subpopulation of layer 5 pyramidal neurons in the prefrontal cortex. J Neurosci 32:10516–21. doi:10.1523/JNEUROSCI.1367-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mcnamara CG, Tejero-Cantero Á, Trouche S et al (2014) Dopaminergic neurons promote hippocampal reactivation and spatial memory persistence. Nat Neurosci 17:1658–60. doi:10.1038/nn.3843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fernández-Novoa L, Cacabelos R (2001) Histamine function in brain disorders. Behav Brain Res 124:213–33

    Article  PubMed  Google Scholar 

  12. Cacabelos R, Yamatodani A, Niigawa H et al (1989) Brain histamine in Alzheimer’s disease. Methods Find Exp Clin Pharmacol 11:353–60

    CAS  PubMed  Google Scholar 

  13. Panula P, Rinne J, Kuokkanen K et al (1998) Neuronal histamine deficit in Alzheimer’s disease. Neuroscience 82:993–7

    Article  CAS  PubMed  Google Scholar 

  14. Mazurkiewicz-Kwilecki IM, Nsonwah S (1989) Changes in the regional brain histamine and histidine levels in postmortem brains of Alzheimer patients. Can J Physiol Pharmacol 67:75–8

    Article  CAS  PubMed  Google Scholar 

  15. Medhurst AD, Roberts JC, Lee J et al (2009) Characterization of histamine H3 receptors in Alzheimer’s disease brain and amyloid over-expressing TASTPM mice. Br J Pharmacol 157:130–8. doi:10.1111/j.1476-5381.2008.00075.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pillot C, Heron A, Cochois V et al (2002) A detailed mapping of the histamine H(3) receptor and its gene transcripts in rat brain. Neuroscience 114:173–93

    Article  CAS  PubMed  Google Scholar 

  17. Bitner RS, Markosyan S, Nikkel AL, Brioni JD In-vivo histamine H3 receptor antagonism activates cellular signaling suggestive of symptomatic and disease modifying efficacy in Alzheimer’s disease. Neuropharmacology 60:460–6. doi: 10.1016/j.neuropharm.2010.10.026

  18. Brioni JD, Esbenshade TA, Garrison TR et al (2011) Discovery of histamine H3 antagonists for the treatment of cognitive disorders and Alzheimer’s disease. J Pharmacol Exp Ther 336:38–46. doi:10.1124/jpet.110.166876

    Article  CAS  PubMed  Google Scholar 

  19. Chazot PL (2010) Therapeutic potential of histamine H3 receptor antagonists in dementias. Drug News Perspect 23:99–103. doi:10.1358/dnp.2010.23.2.1475899

    Article  CAS  PubMed  Google Scholar 

  20. Franco R, Martínez-Pinilla E, Lanciego JLJL, Navarro G (2016) Basic pharmacological and structural evidence for class A G-protein-coupled receptor heteromerization. Front Pharmacol In press:76. doi: 10.3389/fphar.2016.00076

  21. Borroto-Escuela DO, Romero-Fernandez W, Garriga P et al (2013) G protein-coupled receptor heterodimerization in the brain. Methods Enzymol 521:281–294. doi:10.1016/B978-0-12-391862-8.00015-6

    Article  CAS  PubMed  Google Scholar 

  22. Moreno E, Hoffmann H, Gonzalez-Sepúlveda M et al (2011) Dopamine D1-histamine H3 receptor heteromers provide a selective link to MAPK signaling in GABAergic neurons of the direct striatal pathway. J Biol Chem 286:5846–54. doi:10.1074/jbc.M110.161489

    Article  CAS  PubMed  Google Scholar 

  23. Fiorentini C, Gardoni F, Spano P et al (2003) Regulation of dopamine D1 receptor trafficking and desensitization by oligomerization with glutamate N-methyl-D-aspartate receptors. J Biol Chem 278:20196–20202. doi:10.1074/jbc.M213140200

    Article  CAS  PubMed  Google Scholar 

  24. Lee FJS, Xue S, Pei L et al (2002) Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor. Cell 111:219–30

    Article  CAS  PubMed  Google Scholar 

  25. Wang M, Wong AH, Liu F (2012) Interactions between NMDA and dopamine receptors: a potential therapeutic target. Brain Res 1476:154–63. doi:10.1016/j.brainres.2012.03.029

    Article  CAS  PubMed  Google Scholar 

  26. Wilkinson D, Wirth Y, Goebel C (2014) Memantine in patients with moderate to severe Alzheimer’s disease: meta-analyses using realistic definitions of response. Dement Geriatr Cogn Disord 37:71–85. doi:10.1159/000353801

    Article  CAS  PubMed  Google Scholar 

  27. Wang D, Jacobs SA, Tsien JZ (2014) Targeting the NMDA receptor subunit NR2B for treating or preventing age-related memory decline. Expert Opin Ther Targets 18:1121–30. doi:10.1517/14728222.2014.941286

    Article  CAS  PubMed  Google Scholar 

  28. Navarro G, Cordomí A, Zelman-Femiak M et al (2016) Quaternary structure of a G-protein-coupled receptor heterotetramer in complex with Gi and Gs. BMC Biol 14:26. doi:10.1186/s12915-016-0247-4

    Article  PubMed  PubMed Central  Google Scholar 

  29. Rodrigues RJ, Almeida T, Díaz-Hernández M et al (2016) Presynaptic P2X1-3 and α3-containing nicotinic receptors assemble into functionally interacting ion channels in the rat hippocampus. Neuropharmacology 105:241–257. doi:10.1016/j.neuropharm.2016.01.022

    Article  CAS  PubMed  Google Scholar 

  30. Navarro G, Carriba P, Gandía J et al (2008) Detection of heteromers formed by cannabinoid CB1, dopamine D2, and adenosine A2A G-protein-coupled receptors by combining bimolecular fluorescence complementation and bioluminescence energy transfer. ScientificWorldJournal 8:1088–97. doi:10.1100/tsw.2008.136

    Article  CAS  PubMed  Google Scholar 

  31. Navarro G, Moreno E, Aymerich M, et al. (2010) Direct involvement of sigma-1 receptors in the dopamine D1 receptor-mediated effects of cocaine. Proc Natl Acad Sci U S A. doi: 10.1073/pnas.1008911107

  32. Navarro G, Moreno E, Bonaventura J et al (2013) Cocaine inhibits dopamine D2 receptor signaling via sigma-1-D2 receptor heteromers. PLoS One 8, e61245. doi:10.1371/journal.pone.0061245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kaphzan H, O’Riordan KJ, Mangan KP et al (2006) NMDA and dopamine converge on the NMDA-receptor to induce ERK activation and synaptic depression in mature hippocampus. PLoS One 1, e138. doi:10.1371/journal.pone.0000138

    Article  PubMed  PubMed Central  Google Scholar 

  34. Chen J, Rusnak M, Luedtke RR, Sidhu A (2004) D1 dopamine receptor mediates dopamine-induced cytotoxicity via the ERK signal cascade. J Biol Chem 279:39317–30. doi:10.1074/jbc.M403891200

    Article  CAS  PubMed  Google Scholar 

  35. Jeon S-M, Cheon S-M, Bae H-R et al (2010) Selective susceptibility of human dopaminergic neural stem cells to dopamine-induced apoptosis. Exp Neurobiol 19:155–64. doi:10.5607/en.2010.19.3.155

    Article  PubMed  PubMed Central  Google Scholar 

  36. Giménez-Xavier P, Gómez-Santos C, Castaño E et al (2006) The decrease of NAD(P)H has a prominent role in dopamine toxicity. Biochim Biophys Acta 1762:564–74. doi:10.1016/j.bbadis.2006.02.003

    Article  PubMed  Google Scholar 

  37. Sidharthan NP, Minchin RF, Butcher NJ (2013) Cytosolic sulfotransferase 1A3 is induced by dopamine and protects neuronal cells from dopamine toxicity: role of D1 receptor-N-methyl-D-aspartate receptor coupling. J Biol Chem 288:34364–74. doi:10.1074/jbc.M113.493239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Navarro G, Ferre S, Cordomi A et al (2010) Interactions between intracellular domains as key determinants of the quaternary structure and function of receptor heteromers. J Biol Chem 285:27346–27359. doi:10.1074/jbc.M110.115634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Koh JY, Yang LL, Cotman CW (1990) Beta-amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage. Brain Res 533:315–20

    Article  CAS  PubMed  Google Scholar 

  40. Le WD, Colom LV, Xie WJ et al (1995) Cell death induced by beta-amyloid 1–40 in MES 23.5 hybrid clone: the role of nitric oxide and NMDA-gated channel activation leading to apoptosis. Brain Res 686:49–60

    Article  CAS  PubMed  Google Scholar 

  41. Wu J, Anwyl R, Rowan MJ (1995) Beta-amyloid selectively augments NMDA receptor-mediated synaptic transmission in rat hippocampus. Neuroreport 6:2409–13

    Article  CAS  PubMed  Google Scholar 

  42. Passani MB, Blandina P (1998) Cognitive implications for H3 and 5-HT3 receptor modulation of cortical cholinergic function: a parallel story. Methods Find Exp Clin Pharmacol 20:725–33

    Article  CAS  PubMed  Google Scholar 

  43. Grove RA, Harrington CM, Mahler A et al (2014) A randomized, double-blind, placebo-controlled, 16-week study of the H3 receptor antagonist, GSK239512 as a monotherapy in subjects with mild-to-moderate Alzheimer’s disease. Curr Alzheimer Res 11:47–58

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Prof. Isidre Ferrer and Dr. Ester Aso for kindly providing the APP/PS1 transgenic animals used in this work and Dr. Julie Perroy for kindly providing constructs encoding NMDA receptor subunits and fusion proteins containing NMDA receptor subunits.

Funding

None of the authors have received compensation for professional services.

MRR had and has a predoctoral contract from the University of Barcelona. DMD had postdoctoral contracts from the Spanish Government. EM and GN had and have research fellow contracts from CIBERNED (Instituto Carlos III, Ministry of Health, Spanish Government). AC, JM, CL, EIC, VC, and RF had and have academic positions linked to the University of Barcelona.

Author information

Author notes

  1. Peter J. McCormick

    Present address: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK

Authors and Affiliations

  1. Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain

    Mar Rodríguez-Ruiz, Estefanía Moreno, David Moreno-Delgado, Gemma Navarro, Josefa Mallol, Antonio Cortés, Carme Lluís, Enric I. Canela, Vicent Casadó, Peter J. McCormick & Rafael Franco

  2. Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain

    Mar Rodríguez-Ruiz, Estefanía Moreno, David Moreno-Delgado, Gemma Navarro, Josefa Mallol, Antonio Cortés, Carme Lluís, Enric I. Canela, Vicent Casadó, Peter J. McCormick & Rafael Franco

  3. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Diagonal 643, Prevosti Building, 08028, Barcelona, Spain

    Rafael Franco

Authors
  1. Mar Rodríguez-Ruiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Estefanía Moreno
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Moreno-Delgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gemma Navarro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Josefa Mallol
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antonio Cortés
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carme Lluís
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Enric I. Canela
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vicent Casadó
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Peter J. McCormick
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Rafael Franco
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rafael Franco.

Ethics declarations

Animal procedures were conducted according to ethical guidelines (European Communities Council Directive 2010/63/EU) and approved by the animal experimentation ethics committee of the Catalan Government (CEEA-DAAM 6419 and CEEA/DMAH 4049 and 5664).

Conflict of Interest

This work was supported by grants SAF2009-07276 (RF) from Spanish Ministry of Economy and Innovation (MINECO), 2014-SGR-1236 (EIC) from Generalitat de Catalunya and 2140610 (EIC) from the Fundació La Marató de TV3. Some grants may include FEDER funds. PJM was supported by projects RYC-2009-05522, SAF2010-18472 and RG140118. Authors declare no conflict of interests.

Additional information

Mar Rodríguez-Ruiz, Estefanía Moreno, David Moreno-Delgado, Vicent Casadó, Peter J. McCormick and Rafael Franco contributed equally to this work.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

Fig. S1 Bimolecular fluorescence complementation optimization. Different ratios of plasmids encoding fusion proteins constituted by H3 or D1 receptors and either half of the YFP were assayed to optimize fluorescence emission after complementation. HEK293T cells were co-transfected with the indicated amounts of cDNAs and 48 h post-transfection, fluorescence was determined at 530 nm. The optimal combination of cDNAs was obtained using D1R-cYFP and H3R-nYFP (a), where the ratio 1.5 μg and 4 μg, respectively, showed the highest percentage of fluorescence emission respect to non-transfected cells. The inverse combination of cDNAs D1R-nYFP and H3R-cYFP (b) showed no significant differences compared to non-transfected cells in all the tested ratios. As negative controls, other non-interacting pairs of receptors were assayed: serotonin 5HT2B and H3 receptors fused to, respectively, the C-terminal and N-terminal hemi-domains of YFP (c), and cannabinoid CB1 and D1 fused to, respectively, the N-terminal and C-terminal hemi-domains of YFP (d). . All negative controls showed no significant differences compared to non-transfected cells. Values are means ± SEM of 3–5 different experiments. One-way ANOVA followed by Dunnett’s post-hoc test showed significant (*p<0.05, ***p< 0.001,) differences compared to non-transfected cells. (TIFF 1241 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rodríguez-Ruiz, M., Moreno, E., Moreno-Delgado, D. et al. 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. Mol Neurobiol 54, 4537–4550 (2017). https://doi.org/10.1007/s12035-016-9995-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-016-9995-y

Keywords

Search

Navigation