title: On the existence and function of galanin receptor heteromers in the central nervous system.
abstract: Galanin receptor (GalR) subtypes 1-3 linked to central galanin neurons may form heteromers with each other and other types of G protein-coupled receptors in the central nervous system (CNS). These heteromers may be one molecular mechanism for galanin peptides and their N-terminal fragments (gal 1-15) to modulate the function of different types of glia-neuronal networks in the CNS, especially the emotional and the cardiovascular networks. GalR-5-HT1A heteromers likely exist with antagonistic GalR-5-HT1A receptor-receptor interactions in the ascending midbrain raphe 5-HT neuron systems and their target regions. They represent a novel target for antidepressant drugs. Evidence is given for the existence of GalR1-5-HT1A heteromers in cellular models with trans-inhibition of the protomer signaling. A GalR1-GalR2 heteromer is proposed to be a galanin N-terminal fragment preferring receptor (1-15) in the CNS. Furthermore, a GalR1-GalR2-5-HT1A heterotrimer is postulated to explain why only galanin (1-15) but not galanin (1-29) can antagonistically modulate the 5-HT1A receptors in the dorsal hippocampus rich in gal fragment binding sites. The results underline a putative role of different types of GalR-5-HT1A heteroreceptor complexes in depression. GalR antagonists may also have therapeutic actions in depression by blocking the antagonistic GalR-NPYY1 receptor interactions in putative GalR-NPYY1 receptor heteromers in the CNS resulting in increases in NPYY1 transmission and antidepressant effects. In contrast the galanin fragment receptor (a postulated GalR1-GalR2 heteromer) appears to be linked to the NPYY2 receptor enhancing the affinity of the NPYY2 binding sites in a putative GalR1-GalR2-NPYY2 heterotrimer. Finally, putative GalR-α2-adrenoreceptor heteromers with antagonistic receptor-receptor interactions may be a widespread mechanism in the CNS for integration of galanin and noradrenaline signals also of likely relevance for depression.
authors.affiliation: Department of Neuroscience, Karolinska Institutet Stockholm, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
authors.forename: Dasiel O
authors.initials: DO
authors.lastname: Borroto-Escuela
authors.forename: Wilber
authors.initials: W
authors.lastname: Romero-Fernandez
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Tarakanov
authors.forename: Feliciano
authors.initials: F
authors.lastname: Calvo
authors.forename: Pere
authors.initials: P
authors.lastname: Garriga
authors.forename: Mercé
authors.initials: M
authors.lastname: Tena
authors.forename: Manuel
authors.initials: M
authors.lastname: Narvaez
authors.forename: Carmelo
authors.initials: C
authors.lastname: Millón
authors.forename: Concepción
authors.initials: C
authors.lastname: Parrado
authors.forename: Francisco
authors.initials: F
authors.lastname: Ciruela
authors.forename: Luigi F
authors.initials: LF
authors.lastname: Agnati
authors.forename: José A
authors.initials: JA
authors.lastname: Narvaez
authors.forename: Zaida
authors.initials: Z
authors.lastname: Díaz-Cabiale
keywords: 5HT1A; GPCRs; NPY receptors; allosteric modulator; galanin receptors; heteromers