Existence of Brain 5-HT1A-5-HT2A Isoreceptor Complexes with Antagonistic Allosteric Receptor-Receptor Interactions Regulating 5-HT1A Receptor Recognition

  • ACS Omega. 2017 Aug 31;2(8):4779-4789. doi: 10.1021/acsomega.7b00629.
Dasiel O Borroto-Escuela  1  2  3 ,  Xiang Li  1  4 ,  Alexander O Tarakanov  5 ,  David Savelli  1  3 ,  Manuel Narváez  6 ,  Kirill Shumilov  6 ,  Yuniesky Andrade-Talavera  1 ,  Antonio Jimenez-Beristain  7 ,  Bartosz Pomierny  1 ,  Zaida Díaz-Cabiale  6 ,  Riccardo Cuppini  3 ,  Patrizia Ambrogini  3 ,  Maria Lindskog  1 ,  Kjell Fuxe  1
Affiliations
  • 1. Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Neuronal Oscillations Lab, Karolinska Institutet, 17177 Stockholm, Sweden.
  • 2. Observatorio Cubano de Neurociencias, Grupo Bohío-Estudio, Zayas 50, 62100 Yaguajay, Cuba.
  • 3. Department of Biomolecular Science, Section of Physiology, University of Urbino, Campus Scientifico Enrico Mattei, via Ca' le Suore 2, I-61029 Urbino, Italy.
  • 4. College of Life Sciences, Jilin University, Qianjin Street No. 2699, 130012 Changchun, China.
  • 5. Russian Academy of Sciences, St. Petersburg Institute for Informatics and Automation, 199178 Saint Petersburg, Russia.
  • 6. Facultad de Medicina, Instituto de Investigación Biomédica de Málaga and Departamento de Biología Celular, Universidad de Málaga, Campus de Teatinos s/n, 29071 Málaga, España.
  • 7. Department of Physiology and Pharmacology, Karolinska Institutet, Von Eulers väg 8, 17177 Stockholm, Sweden.
PMID: 28920103 DOI: 10.1021/acsomega.7b00629
Abstract

Studies on serotonin-selective reuptake inhibitors have established that disturbances in the ascending 5-HT neuron systems and their 5-HT Receptor subtypes and collateral networks to the forebrain contribute to the etiology of major depression and are targets for treatment. The therapeutic action of serotonin-selective reuptake inhibitors is of proven effectiveness, but the mechanisms underlying their effect are still unclear. There are many 5-HT subtypes involved; some need to be blocked (e.g., 5-HT2A, 5-HT3, and 5-HT7), whereas Others need to be activated (e.g., postjunctional 5-HT1A and 5-HT4). These state-of-the-art developments are in line with the hypothesis that the development of major depression can involve an imbalance of the activity between different types of 5-HT isoreceptors. In the current study, using in situ proximity ligation assay (PLA), we report evidence for the existence of brain 5-HT1A-5-HT2A isoreceptor complexes validated in cellular models with bioluminescence resonance energy transfer (BRET2) assay. A high density of PLA-positive clusters visualizing 5-HT1A-5-HT2A isoreceptor complexes was demonstrated in the pyramidal cell layer of the CA1-CA3 regions of the dorsal hippocampus. A marked reduction in the density of PLA-positive clusters was observed in the CA1 and CA2 regions 24 h after a forced swim test session, indicating the dynamics of this 5-HT isoreceptor complex. Using a bioinformatic approach, previous work indicates that receptors forming heterodimers demonstrate triplet amino acid homologies. The receptor interface of the 5-HT1A-5-HT2A isoreceptor dimer was shown to contain the LLG and QNA protriplets in the transmembrane and intracellular domain, respectively. The 5-HT2A agonist TCB2 markedly reduced the affinity of the 5-HT1A agonist ipsapirone for the 5-HT1A agonist binding sites in the frontal lobe using the 5-HT1A radioligand binding assay. This action was blocked by the 5-HT2A antagonist ketanserin. It is proposed that the demonstrated 5-HT1A-5-HT2A isoreceptor complexes may play a role in depression through integration of 5-HT recognition, signaling and trafficking in the plasma membrane in two major 5-HT Receptor subtypes known to be involved in depression. Antagonistic allosteric receptor-receptor interactions appear to be involved in this integrative process.

Products