Activation of the galanin receptor 2 (GalR2) protects the hippocampus from neuronal damage

Abstract

Expression of the neuropeptide galanin is up-regulated in many brain regions following nerve injury and in the basal forebrain of patients with Alzheimer's disease. We have previously demonstrated that galanin modulates hippocampal neuronal survival, although it was unclear which receptor subtype(s) mediates this effect. Here we report that the protective role played by galanin in hippocampal cultures is abolished in animals carrying a loss-of-function mutation in the second galanin receptor subtype (GalR2-MUT). Exogenous galanin stimulates the phosphorylation of the serine/ threonine kinase Akt and extracellular signal-regulated kinase (ERK) in wild-type (WT) cultures by 435 ± 5% and 278 ± 2%, respectively. The glutamate-induced activation of Akt was abolished in cultures from galanin knockout animals, and was markedly attenuated in GalR2-MUT animals, compared with WT controls. In contrast, similar levels of glutamate-induced ERK activation were observed in both loss-of-function mutants, but were further increased in galanin over-expressing animals. Using specific inhibitors of either ERK or Akt confirms that a GalR2-dependent modulation in the activation of the Akt and ERK signalling pathways contributes to the protective effects of galanin. These findings imply that the rise in endogenous galanin observed either after brain injury or in various disease states is an adaptive response that reduces apoptosis by the activation of GalR2, and hence Akt and ERK.

A role for galanin in human and experimental inflammatory demyelination

“…Furthermore the addition of exogenous galanin peptide or the GalR2/3-specific agonist Gal2-11 reduced the amount of cell death when co-administered with either glutamate or staurosporine in WT primary hippocampal cultures (15). We have recently extended these findings by demonstrating that organotypic hippocampal cultures from mice with a loss-of-function mutation in GalR2 (GalR2-MUT) treated with glutamate show more cell death than WT controls and this cannot be rescued with the addition of either exogenous galanin or Gal2-11 (16). In support of these findings, studies by Pirondi and colleagues have shown that glutamate induced upregulation of c-fos can be reversed using galanin or Gal2-11 (17).…”

“…All three subtypes are expressed by differing neuronal populations in the brain [reviewed in (30,31)], and in addition Su and colleagues have shown that GalR2 (but not GalR1 or GalR3) is expressed by rat primary microglia and the murine BV2 and rat HAPI glial clonal cell lines (32). Consistent with a neuroprotective role, GalR2 (unlike GalR1 or GalR3) is known to signal via G q/11 to activate phospholipase C and protein kinase C (33,34) and hence ERK (16). Previous studies have also shown that hippocampal neuroprotection is dependent in part upon activation of ERK (35,36) and ERK KO mice have increased susceptibility to EAE (37).…”

“…Importantly, it is now the consensus view that the clinical severity of inflammatory demyelination, in both mouse and man, is likely to be a consequence of the degree of axonal degeneration (24)(25)(26). It is therefore of considerable interest that our prior work indicates that galanin exerts neuroprotective effects after injury (15) and that these activities have been shown to be principally mediated via neuronally expressed GalR2 (16). In this study, we have also identified that in the context of central demyelination in patients with MS, galanin was expressed not by neurons, as had been identified in other contexts such as kainate-induced neuronal injury, but by microglia, probably reflecting the predominant white matter focus of pathology in this instance (27).…”

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

“…Activation of GAL 2 is capable of stimulating the MAPK/ ERK pathway in a PTX-sensitive, PKC-dependent fashion, indicative of coupling to a G 0 protein in GAL 2 -transfected cell lines (Wang et al, 1998c). Endogenous GAL 2 -induced activation of the MAPK/ERK pathway via PKC has been reported in rodent hippocampal neurons (Hawes et al, 2006;Elliott-Hunt et al, 2007), rat microglial cells (Ifuku et al, 2011), rat PC12 pheochromocytoma cells (Hawes et al, 2006), and human small-cell lung cancer (SCLC) cells (Seufferlein and Rozengurt, 1996), although in the latter, MAPK/ ERK pathway activation can also occur independently of PKC (Wittau et al, 2000). GAL 2 predominantly couples to a G q/11 -type G protein, leading to phospholipase C activation, which stimulates Ca 2+ release via inositol phosphate hydrolysis and opens Ca 2+ -dependent ion channels in a PTXresistant manner, in both GAL 2 -transfected cell lines (Smith et al, 1997b;Borowsky et al, 1998;Fathi et al, 1998;Pang et al, 1998;Wang et al, 1998c) and GAL 2 -expressing rat microglial cells (Ifuku et al, 2011).…”

Myenteric plexuses atrophy in the vicinity of colorectal cancer tissue is not caused by apoptosis or necrosis

“…Thus, in many models of intestinal pathology galanin content and the number of GAL-Ir neurons may be altered suggesting the adaptive possibilities of the enteric neurons. This may be associated with the neuroprotective action of galanin that was well-documented in many experimental models of brain, nerve and neurons' injury [3,[8][9][10].…”