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.

Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray

“…More recent studies demonstrating galanin receptor heteromers have introduced a further degree of complexity in interpreting galaninergic mechanisms in the brain (96). In addition to GALR1 and 5-HT1A receptor heterodimers (97), an involvement of the galanin (1-15) fragment in mood regulation via GALR1 and GALR2 heterocomplexes in the dorsal HPC and DR has been reported (98).…”

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

“…GAL 2 also undergoes internalization upon ligand binding (Xia et al, 2004(Xia et al, , 2005b. There is also increasing evidence that different galanin receptors can form heteromers, at least in the CNS (Fuxe et al, 2012), leading to altered recognition of galanin ligands. Moreover, putative heteromers of galanin receptors with other GPCRs have been described, including GAL 1 with a 5-HT receptor, Y 1 and Y 2 (NPY) receptors, a 2 -adrenoceptor (Fuxe et al, 2008(Fuxe et al, , 2012, and dopamine D 1 -like receptors (D 1 and D 5 ), but not GAL 2 (Moreno et al, 2011).…”

“…There is also increasing evidence that different galanin receptors can form heteromers, at least in the CNS (Fuxe et al, 2012), leading to altered recognition of galanin ligands. Moreover, putative heteromers of galanin receptors with other GPCRs have been described, including GAL 1 with a 5-HT receptor, Y 1 and Y 2 (NPY) receptors, a 2 -adrenoceptor (Fuxe et al, 2008(Fuxe et al, , 2012, and dopamine D 1 -like receptors (D 1 and D 5 ), but not GAL 2 (Moreno et al, 2011). This latter study provides strong evidence that D 1 -like/GAL 1 receptor heteromers integrate signals of the monoamine and neuropeptide transmitter systems to modulate hippocampal cholinergic neurotransmission.…”

“…Recently, it was postulated that GAL 1 interacts with GAL 2 to form heterotrimers with the Y 2 receptor or angiotensin II type I receptor in the NTS to integrate cardiovascular responses (Fuxe et al, 2012). Furthermore, it was proposed that galanin receptors form heteromers with other neuromodulatory receptors involved in central cardiovascular regulation such as 5-HT 1A receptor, a 2 -adrenoceptor or Y 1 receptor (DiazCabiale et al, 2010).…”

On the role of the extracellular space on the holistic behavior of the brain

“…For example, a VT peptide can be modified or even split by ecto-enzymes (Konkoy and Davis, 1996) with the possible formation of different sets of fragments from the same parent peptide that can differentially modulate the various cells of CCNs eliciting different types of integrative responses (Agnati and Fuxe, 2000;Agnati et al, 2004aAgnati et al, , 2005cFuxe et al, 2007a). Fuxe et al (2012) suggested that galanin (1-15) can play a specific role in depression in view of its high diffusion capabilities [lower molecular weight with respect to galanin (1-29)] and hence its possible extra-synaptic modulatory actions on GalR-5-HT1A heteroreceptor complexes. Such a view underlines our proposal that GMN by regulating diffusion of VT signals in the ECS has a fundamental role in the brain holistic behavior.…”