Galanin inhibits acetylcholine release from rat cerebral cortex via a pertussis toxin-sensitive Giprotein

doi:10.1054/npep.1999.0024

Neuropeptides

Volume 33, Issue 3, June 1999, Pages 197-205

https://doi.org/10.1054/npep.1999.0024 Get rights and content

Abstract

Galanin has been implicated in various physiological functions including memory, feeding and pain perception. Using rat cerebral cortical slices and synaptosome preparations incubated with [³H]choline in Kreb’s-Ringer solution, galanin was shown to inhibit both spontaneous and K⁺-stimulated [³H]ACh release in a concentration-related manner [EC₅₀= 35 nM]. The galanin-mediated inhibition on spontaneous and K⁺-stimulated [³H]ACh release was respectively regulated by pertussis toxin-sensitive G_αi3and G_αi1. These suggest that galanin is a negative modulator of cortical cholinergic function and most probably acting on presynaptic cholinergic terminals. Although galantide blocked the galanin-mediated inhibitory effect on [³H]ACh release, it mimicked galanin in blocking K⁺-stimulated [³H]ACh release, indicating that galantide may have a more complicated pharmacology than being a galanin receptor antagonist. In addition, we demonstrate that galanin and β-amyloid peptide_1–42synergistically attenuated K⁺-evoked [³H]ACh release from synaptosomes prepared from rat cerebral cortex. Since galanin is increased in Alzheimer’s disease brain, our results suggest that galanin may be involved in cholinergic dysfunctions that occur in Alzheimer’s disease.

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Cited by (52)

Neuroanatomical characterization of the G protein-coupled receptor activity evoked by galanin-related ligands
2023, Journal of Chemical Neuroanatomy
Galanin neuropeptide is distributed throughout the mammalian nervous system modulating a plethora of diverse physiological functions, including nociception, cognition and neuroendocrine regulation. The regulation of the galaninergic system is an interesting approach for the treatment of different diseases associated to those systems. Nevertheless, the pharmacological selectivity and activities of some galanin receptor (GalR) ligands are still in discussion and seem to depend on the dose, the receptor subtype and the second messengers to which they are coupled at different brain areas. The activity of different GalR ligands on G_i/o proteins, was evaluated by the guanosine 5′-(γ-[³⁵S]thio)triphosphate ([³⁵S]GTPγS) autoradiography in vitro assay applied to rat brain tissue slices in the presence of galanin, M15, M35, M40, gal(2−11) or galnon. The enhancement of the [³⁵S]GTPγS binding induced by the chimerical peptides M15, M35 and M40 was similar to that produced by Gal in those brain areas showing the highest stimulations, such as dorsal part of the olfactory nucleus and ventral subiculum. In contrast to these peptides, using gal(2−11) no effect was measured on G_i/o protein coupling in areas of the rat brain with high GalR₁ density such as posterior hypothalamic nucleus and amygdala, indicating low selectivity for GalR₁ receptors. The effects evoked by the non-peptide ligand, galnon, were different from those induced by galanin, behaving as agonist or antagonist depending on the brain area, but the stimulations were always blocked by M35. Thus, the activity of most used GalR ligands on G_i/o protein mediated signalling is complex and depends on the brain area. More selective and potent GalR ligands are necessary to develop new treatments aimed to modulate the galaninergic system.
Compartmental modeling and analysis of the effect of β-amyloid on acetylcholine neurocycle via choline leakage hypothesis
2021, Computers and Chemical Engineering
In this paper, the effect of β-amyloid (Aβ) oligomer aggregates on Acetylcholine (ACh) neurocycle of human brain and its relation to Alzheimer's disease (AD) are investigated through a two-enzyme/two-compartment (2E2C) diffusion mathematical model whereby compartment 1 represents the presynaptic neuron while compartment 2 represents the postsynaptic neuron and postsynaptic cleft. It is found that Aβ aggregates induce choline leakage from the presynaptic neurons (compartment 1) leading to a reduction in choline content in both compartments. The lowering in choline levels in each compartment is promoted with the increase in the inlet Aβ oligomers which create more channels and pores in the presynaptic membrane. In addition, it is found that both the rates of ACh synthesis and hydrolysis were affected negatively by the increase in the levels of Aβ oligomers. Furthermore, the levels of ACh in both compartments decreased while the level of Aβ oligomers increased. However, the acetate concentration in compartment 1 increased but the acetate level in compartment 2 decreased. These results are compatible with the low levels of both ACh and choline in the neuron tissues of Alzheimer's disease (AD) brains through choline leakage hypothesis. Also, the model shows the significant effect of inhibiting Aβ aggregation as a promising therapeutic mechanism to mitigate cholinergic diseases. The model suggests that Aβ oligomers exert neuroinflammatory and toxic effect against the ACh neurocycle. The paper suggests that development of therapeutic agents capable of inhibiting toxic Aβ aggregations and maintaining choline substrates in neurons is necessary to provide a neuroprotective effect, cholinergic transmission, and maintain reasonable levels of ACh.
Synaptosome as a tool in Alzheimer's disease research
2020, Brain Research
Citation Excerpt :
This finding might indicate a compensatory reaction of the surviving synapses in view of the widespread degeneration of cholinergic signalling; this hypothesis was further supported by the study of Wang et al. (2009). Synergistic action of Aβ and galanin (a relatively unstudied neuropeptide) in attenuation of acetylcholine release from rat cerebrocortical synaptosomes suggests the potential role of this peptide in inducing cholinergic dysfunction in AD pathogenesis, particularly in view of the observations of increased expression of galanin in the disease conditions (Wang et al., 1999). Further understanding of the effects of soluble Aβ peptides on cholinergic signalling in the amyloid pathology in AD comes from a study utilizing crude synaptosomal preparation from rat hippocampus; Aβ1-40 was found to inhibit both nicotinic and muscarinic evoked dopamine overflow, although by different mechanisms.
Synapse dysfunction is an integral feature of Alzheimer’s disease (AD) pathophysiology. In fact, prodromal manifestation of structural and functional deficits in synapses much prior to appearance of overt pathological hallmarks of the disease indicates that AD might be considered as a degenerative disorder of the synapses. Several research instruments and techniques have allowed us to study synaptic function and plasticity and their alterations in pathological conditions, such as AD. One such tool is the biochemically isolated preparations of detached and resealed synaptic terminals, the “synaptosomes”. Because of the preservation of many of the physiological processes such as metabolic and enzymatic activities, synaptosomes have proved to be an indispensable ex vivo model system to study synapse physiology both when isolated from fresh or cryopreserved tissues, and from animal or human post-mortem tissues. This model system has been tremendously successful in the case of post-mortem tissues because of their accessibility relative to acute brain slices or cultures. The current review details the use of synaptosomes in AD research and its potential as a valuable tool in furthering our understanding of the pathogenesis and in devising and testing of therapeutic strategies for the disease.
Effects of galanin subchronic treatment on memory and muscarinic receptors
2015, Neuroscience
The cholinergic pathways, which originate in the basal forebrain and are responsible for the control of different cognitive processes including learning and memory, are also regulated by some neuropeptides. One of these neuropeptides, galanin (GAL), is involved in both neurotrophic and neuroprotective actions. The present study has evaluated in rats the effects on cognition induced by a subchronic treatment with GAL by analyzing the passive avoidance response, and the modulation of muscarinic cholinergic receptor densities and activities. [³H]-N-methyl-scopolamine, [³H]-oxotremorine, and [³H]-pirenzepine were used to quantify the density of muscarinic receptors (MRs) and the stimulation of the binding of guanosine 5′-(γ-[³⁵S]thio)triphosphate by the muscarinic agonist, carbachol, to determine their functionality.
Some cognitive deficits that were induced by the administration of artificial cerebrospinal fluid (aCSF) (i.c.v. aCSF 2 μl/min, once a day for 6 days) were not observed in the animals also treated with GAL (i.c.v. 1.5 mmol in aCSF, 2 μl/min, once a day for 6 days). GAL modulates the changes in M₁ and M₂ MR densities observed in the rats treated with aCSF, and also increased their activity mediated by G_i/o proteins in specific areas of the dorsal and ventral hippocampus. The subchronic administration of the vehicle was also accompanied by an increased number of positive fibers and cells for GAL around the cortical tract of the cannula used, but that was not the case in GAL-treated rats. In addition, the increase of GAL receptor density in the ventral hippocampus and entorhinal cortex in the aCSF group was avoided when GAL was administered. The number of acetylcholinesterase (AChE)-positive neurons was decreased in the nucleus basalis of Meynert of both GAL- and aCSF-treated animals. In summary, GAL improves memory-related abilities probably through the modulation of MR density and/or efficacy in hippocampal areas.
Regulation of the mesolimbic dopamine circuit by feeding peptides
2015, Neuroscience
Citation Excerpt :
The mechanisms associated with increased CPP for drugs in galanin KO mice are unclear; however, these mice show a significant increase in ERK activation in the VTA and NAc (Narasimhaiah et al., 2009). Furthermore, inhibitory G-protein-coupled GalR1 are expressed on cholinergic terminals and decrease Ach release (Wang et al., 1999), thus galanin may indirectly reduce activity of dopamine neurons providing an alternate mechanism for galanin-mediated inhibition of reward seeking. Galanin’s inhibitory role in reward seeking is in contrast to it promotion of ingestive behavior for caloric substances, like alcohol or dietary fat (Barson et al., 2010).
Polypeptides produced in the gastrointestinal tract, stomach, adipocytes, pancreas and brain that influence food intake are referred to as ‘feeding-related’ peptides. Most peptides that influence feeding exert an inhibitory effect (anorexigenic peptides). In contrast, only a few exert a stimulating effect (orexigenic peptides), such as ghrelin. Homeostatic feeding refers to when food consumed matches energy deficits. However, in western society where access to palatable energy-dense food is nearly unlimited, food is mostly consumed for non-homeostatic reasons. Emerging evidence implicates the mesocorticolimbic circuitry, including dopamine neurons of the ventral tegmental area (VTA), as a key substrate for non-homeostatic feeding. VTA dopamine neurons encode cues that predict rewards and phasic release of dopamine in the ventral striatum motivates animals to forage for food. To elucidate how feeding-related peptides regulate reward pathways is of importance to reveal the mechanisms underlying non-homeostatic or hedonic feeding. Here, we review the current knowledge of how anorexigenic peptides and orexigenic peptides act within the VTA.
Galanin promotes neuronal differentiation from neural progenitor cells in vitro and contributes to the generation of new olfactory neurons in the adult mouse brain
2014, Experimental Neurology
Galanin is a pleiotropic neuropeptide widely expressed in the nervous system. It plays a role in many diverse physiological functions – including nociception, cognition and metabolism regulation – and acts as neurotrophic/neuroprotective factor for several neuronal populations. In this article we sought to determine the role of galanin on neural stem cell function and its contribution to the plasticity of the nervous system. Here we show that galanin and its receptors are expressed in neural progenitor cells (NPCs) isolated from the developing striatum. Stimulation with galanin results in upregulation of Bcl-Xl, Bcl-2, Mash-1 and Olig-2 that are part of well known pro-survival/pro-neuronal signalling pathways. Accordingly, treatment with galanin increases the number of neurons upon differentiation from these progenitors. We then show that these effects are recapitulated in NPCs isolated from the adult subventricular zone (SVZ), where galanin increases the total number of neurons and the number of newly-generated neurons upon differentiation in vitro. The significance of these findings is highlighted in the adult brain where loss of galanin leads to a marked decrease in the rate of adult SVZ neurogenesis and a reduction in the number of newly generated cells in the olfactory bulb. Interestingly, Gal-KO mice display normal performances in simple tasks of olfactory detection and discrimination, which points to the existence of a certain degree of redundancy in SVZ neurogenesis. Our findings establish the role of galanin as a modulator of neural stem cell function and support the importance of galanin for brain plasticity and repair.

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^☆: Correspondence to : Dr Hoau-Yan Wang, The R.W. Johnson Pharmaceutical Research Institute, Rm 345, Research Building McKean and Welsh Roads, Spring House, PA 19477, USA. Tel: +1 215 628 5242; Fax: +1 215 628 3297; E-mail: [email protected]

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Regular ArticleGalanin inhibits acetylcholine release from rat cerebral cortex via a pertussis toxin-sensitive Giprotein☆

Abstract

Peptides

Biochem Biophys Res Commun

Identification of different pharmacophores within galanin for the three galanin receptor subtypes. J Biol Chem

Biochem Biophys Res Commun

Brain Res

Life Sci

Mol Brain Res

Biochem Biophys Res Comm

Peptide (N.Y.)

Eur J Pharmacol

Exp Neurol

Int J Biochem Cell Biol

Eur J Med Chem

Eur J Pharmacol

Neurosci

Trends Neurosci

Neurosci Lett

Brain Res

Exp Neurol

Neurosci

Galanin-A neuroendocrine peptide

Critical Rev Neurobiol

Autoradiographic quantitiation and anatomical mapping of125I-galanin binding sites in the rat central nervous system

J Chem Neuroanat

Autoradiographic mapping of galanin receptors in the monkey brain

J Chem Neuroanat

Mechanism of galanin-inhibited insulin release: occurrence of a pertussis toxin-sensitive inhibition of adenylate cyclase

Eur J Biochem

Galanin receptor-mediated inhibition of glutamate release in the arcuate nucleus of the hypothalamus

J Neurosci

The behavioral effects of intrathecal galanin on tests of thermal and mechanical nociception in the rat

Acta Physiol Scad

Regular Article
Galanin inhibits acetylcholine release from rat cerebral cortex via a pertussis toxin-sensitive G_iprotein☆

Autoradiographic quantitiation and anatomical mapping of¹²⁵I-galanin binding sites in the rat central nervous system