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Adenosine A1-Dopamine D1 Receptor Heteromers Control the Excitability of the Spinal Motoneuron

  • Marla Rivera-Oliver
  • Estefanía Moreno
  • Yocasta Álvarez-Bagnarol
  • Christian Ayala-Santiago
  • Nicole Cruz-Reyes
  • Gian Carlo Molina-Castro
  • Stefan Clemens
  • Enric I. Canela
  • Sergi Ferré
  • Vicent Casadó
  • Manuel Díaz-Ríos
Article

Abstract

While the role of the ascending dopaminergic system in brain function and dysfunction has been a subject of extensive research, the role of the descending dopaminergic system in spinal cord function and dysfunction is just beginning to be understood. Adenosine plays a key role in the inhibitory control of the ascending dopaminergic system, largely dependent on functional complexes of specific subtypes of adenosine and dopamine receptors. Combining a selective destabilizing peptide strategy with a proximity ligation assay and patch-clamp electrophysiology in slices from male mouse lumbar spinal cord, the present study demonstrates the existence of adenosine A1-dopamine D1 receptor heteromers in the spinal motoneuron by which adenosine tonically inhibits D1 receptor-mediated signaling. A1-D1 receptor heteromers play a significant control of the motoneuron excitability, represent main targets for the excitatory effects of caffeine in the spinal cord and can constitute new targets for the pharmacological therapy after spinal cord injury, motor aging-associated disorders and restless legs syndrome.

Keywords

Adenosine A1 receptor Dopamine D1 receptor Receptor heteromers Spinal cord Motoneuron 

Notes

Acknowledgements

We would like to thank Dr. Thomas Cleland (Cornell University) for providing the scripts for electrophysiological data analysis, Joselyne Álvarez-González, Garrett Seale, Amelia Merced, and Andrea Husch for technical assistance.

Funding Information

This work was supported by COBRE Center for Neuroplasticity (NIH NIGMS 5P20GM103642-05), intramural funds of the National Institute of Drug Abuse, NSF (DBI-1337284), RCMI (NIMHD 8G12-MD007600), RISE Program (5R25GM061151), and grants from the Spanish “Ministerio de Economía y Competitividad” and European Regional Development Funds of the European Union (SAF2014-54840-R and SAF2017-87629-R), the “Fundació La Marató de TV3” (20140610), and Government of Catalonia (2017-SGR-1497).

Supplementary material

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Authors and Affiliations

  • Marla Rivera-Oliver
    • 1
  • Estefanía Moreno
    • 2
  • Yocasta Álvarez-Bagnarol
    • 1
  • Christian Ayala-Santiago
    • 1
  • Nicole Cruz-Reyes
    • 1
  • Gian Carlo Molina-Castro
    • 1
  • Stefan Clemens
    • 3
  • Enric I. Canela
    • 2
  • Sergi Ferré
    • 4
  • Vicent Casadó
    • 2
  • Manuel Díaz-Ríos
    • 1
  1. 1.Department of Anatomy and Neurobiology and Institute of NeurobiologyUniversity of Puerto Rico, Medical SciencesSan JuanPuerto Rico
  2. 2.Center for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED) and Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of BarcelonaUniversity of BarcelonaBarcelonaSpain
  3. 3.Department of Physiology, Brody School of MedicineEast Carolina UniversityGreenvilleUSA
  4. 4.Integrative Neurobiology Section, Intramural Research ProgramNational Institute on Drug Abuse, National Institutes of HealthBaltimoreUSA

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