Galanin receptor-1 modulates 5-hydroxtryptamine-1A signaling via heterodimerization.
Previous biochemical, cardiovascular and behavioral work has given evidence for the existence of antagonistic galanin receptor-5-HT1A receptor interactions in the brain. In this study we investigated the existence of GalR1-5-HT1A receptor heteromers and their functional characteristics. In mammalian cells transfected with GFP2-tagged 5-HT1A receptor and YFP-tagged GalR1 receptor, a proximity-based fluorescence resonance energy transfer technique was used and it has been demonstrated that GalR1-5-HT1A receptors heteromerize. Furthermore, signaling by either the mitogen-activated protein kinase (MAPK) or adenylyl cyclase (AC) pathways by these heteromers indicates a trans-inhibition phenomenon through their interacting interface via allosteric mechanisms that block the development of an excessive activation of G(i/o) and an exaggerated inhibition of AC or stimulation of MAPK activity. The presence of these heteromers in the discrete brain regions is postulated based on the existence of GalR-5-HT1A receptor-receptor interactions previously described in the brain and gives rise to explore possible novel therapeutic strategies for treatment of depression by targeting the GalR1-5-HT1A heteromers.
Borroto-Escuela
Dasiel O
DO
Department of Neuroscience, Karolinska Institutet. Retzius väg 8, 17177 Stockholm, Sweden. Dasiel.Borroto-Escuela@ki.se
Narvaez
Manuel
M
Marcellino
Daniel
D
Parrado
Concepción
C
Narvaez
José Angel
JA
Tarakanov
Alexander O
AO
Agnati
Luigi F
LF
Díaz-Cabiale
Zaida
Z
Fuxe
Kjell
K
D002460:Cell Line; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D055503:Protein Multimerization; D044091:Receptor, Galanin, Type 1 / Q000235:genetics / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D044091:Receptor, Galanin, Type 1; D044282:Receptor, Serotonin, 5-HT1A; D008156:Luciferases