The human galanin receptor: ligand-binding and functional characteristics in the Bowes melanoma cell line

Heuillet, E.; Bouaiche, Zakia; Ménager, Jean; Dugay, P.; Muñoz, N. L.; Dubois, H.; Amiranoff, B.; Crespo, André; Lavayre, Jacques; Blanchard, Jean‐Charles; Doble, Adam

doi:10.1016/0922-4106(94)90080-9

Cited by 55 publications

(25 citation statements)

References 29 publications

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“…Error bars in lower panel indicate S.E. Relative reduction in band intensities are: A␤ 1-11 , 20% (p Ͻ 0.0001); A␤ 10 -20 , 22% (p Ͻ 0.05); A␤ [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] , 92% (p Ͻ 0.001); A␤ [22][23][24][25][26][27][28][29][30][31][32][33][34][35] , 21% (p Ͻ 0.001). Panel E, immunoprecipitation and Western analyses were performed in a similar manner using an equal amount of PC12 cells or PC12 overexpressing APP cell membrane proteins as the starting material in the presence or absence of exogenous A␤ 1-42 (100 nM).…”

Section: Resultsmentioning

confidence: 99%

“…Using the same experimental setup, the effects of galanin, neuropeptide Y (Palomar Research Inc.), A␤ [1][2][3][4][5][6][7][8][9][10][11] , A␤ 10 -20 , A␤ [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] , A␤ [22][23][24][25][26][27][28][29][30][31][32][33][34][35] , or A␤ 40 -1 (Sigma) on complex formation were evaluated separately by including a 100 nM concentration of each peptide in the incubation mixture.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

β-Amyloid1–42 Binds to α7 Nicotinic Acetylcholine Receptor with High Affinity

Wang

Lee

D’Andrea

et al. 2000

Journal of Biological Chemistry

748

393

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Alzheimer's disease pathology is characterized by the presence of neuritic plaques and the loss of cholinergic neurons in the brain. The underlying mechanisms leading to these events are unclear, but the 42-amino acid ␤-amyloid peptide (A␤ 1-42 ) is involved. Immunohistochemical studies on human sporadic Alzheimer's disease brains demonstrate that A␤ 1-42 and a neuronal pentameric cation channel, the ␣7 nicotinic acetylcholine receptor (␣7nAChR), are both present in neuritic plaques and co-localize in individual cortical neurons. Using human brain tissues and cells that overexpress either ␣7nAChR or amyloid precursor protein as the starting material, A␤ 1-42 and ␣7nAChR can be co-immunoprecipitated by the respective specific antibodies, suggesting that they are tightly associated. The formation of the ␣7nAChR⅐A␤ 1-42 complex can be efficiently suppressed by A␤ 12-28 , implying that this A␤ sequence region contains the binding epitope. Receptor binding experiments show that A␤ 1-42 and ␣7nAChR bind with high affinity, and this interaction can be inhibited by ␣7nAChR ligands. Human neuroblastoma cells overexpressing ␣7nAChR are readily killed by A␤ 1-42 , whereas ␣7nAChR agonists such as nicotine and epibatidine offered protection. Because A␤ 1-42 inhibits ␣7nAChR-dependent calcium activation and acetylcholine release, two processes critically involved in memory and cognitive functions, and the distribution of ␣7nAChR correlates with neuritic plaques in Alzheimer's disease brains, we propose that interaction of the ␣7nAChR and A␤ 1-42 is a pivotal mechanism involved in the pathophysiology of Alzheimer's disease.Evidence obtained from familial Alzheimer's disease (AD) 1 patients (1-3) and transgenic animals (4 -7) overexpressing amyloid precursor protein (APP) indicates that A␤ 1-42 is a causal factor of neuritic plaque formation and neurodegeneration in AD. A␤ peptides are known to bind specifically to the scavenger receptors expressed in microglia and macrophages (8, 9) and the ubiquitous receptor for advanced glycation end products (RAGE) (10, 11). A␤ binding to scavenger receptors may induce cell death by generating free radicals (12, 13), whereas binding to RAGE may promote A␤ clearance (10, 11). However, the respective receptor function and distribution pattern for scavenger receptors and RAGE cannot fully explain the A␤ 1-42 -induced pathophysiology observed in AD such as cognitive and memory impairment, in which cholinergic neurons are involved. This suggests that additional physiologically relevant neuronal receptors for A␤ 1-42 may exist.The ␣7 nicotinic acetylcholine receptor (␣7nAChR) is highly expressed in the basal forebrain cholinergic neurons that project to the hippocampus and cortex of normal and AD brains (14, 15), correlating well with brain areas that exhibit neuritic plaques in AD. More importantly, the ␣7nAChR modulates calcium homeostasis and release of the neurotransmitter acetylcholine, two important parameters involved in cognition and memory. We thus investigated the molecular and bioche...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

β-Amyloid1–42 Binds to α7 Nicotinic Acetylcholine Receptor with High Affinity

Wang

Lee

D’Andrea

et al. 2000

Journal of Biological Chemistry

748

393

View full text Add to dashboard Cite

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“…Stably transfected Chinese hamster ovary cells expressing rat GalR2, and Bowes' melanoma cells that express human GalR1 were cultivated as described earlier (30,31).…”

Section: Methodsmentioning

confidence: 99%

“…DRN and LC were dissected from a total of 16 rats͞group and samples from four animals were pooled. Rat brain synaptic membranes (32) and cells were prepared as described (31). Equilibrium binding of [ 125 I]galanin (2,200 Ci͞mmol, PerkinElmer) to hippocampal membrane preparations was performed in 150 l of binding buffer [50 mM Tris⅐Cl, pH 7.4͞5 mM MgCl 2 ͞0.05% (wt͞vol) BSA, supplemented with protease inhibitors].…”

Section: Methodsmentioning

confidence: 99%

A role for galanin in antidepressant actions with a focus on the dorsal raphe nucleus

Lü

Barr²,

Kinney³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

121

131

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Selective serotonin reuptake inhibitors, such as fluoxetine (FLX), are the most commonly used drugs in the treatment of major depression. However, there is a limited understanding of their molecular mechanism of action. Although the acute effect of selective serotonin reuptake inhibitors in elevating synaptic serotonin concentrations is well known, the clinical amelioration of depressive symptoms requires 14 -21 days of treatment, suggesting that numerous other rearrangements of function in the CNS must take place. In the present study, we demonstrated that 14 days of FLX treatment up-regulated galanin mRNA levels by 100% and GalR2-binding sites by 50%, in the rat dorsal raphe nucleus, where galanin coexists with serotonin. Furthermore, a galanin receptor antagonist, M40, attenuated the antidepressant-like effect of FLX in the forced swim test, a rodent preclinical screen commonly used to evaluate antidepressant-like efficacy. Direct activation of galanin receptors by a galanin receptor agonist, galnon, was found to produce an antidepressant-like effect in the same task. Two other antidepressant treatments also affected the galaninergic system in the monoaminergic nuclei: Electroconvulsive shock elevated galanin mRNA levels in dorsal raphe nucleus, whereas sleep deprivation increased galanin mRNA levels in the locus coeruleus, further underlining the connection between activation of the galaninergic system and antidepressant action of various clinically proven treatments. O ur understanding of the molecular mechanism of action of fluoxetine (FLX), beyond its effect of elevating synaptic serotonin [5-hydroxytryptamine (5-HT)] concentration, is limited. The delay in the onset of clinical antidepressant effect suggests that transcriptional and translational events, leading to functional changes in signaling within the major serotoninergic nucleus dorsal raphe nucleus (DRN) and in its projection areas, may be required for these therapeutic effects (1-3). One potential player in mediating the long-term effects of FLX, besides 5-HT, is the neuropeptide galanin. Galanin, through its three G-protein-coupled receptors, GalR1, GalR2, and GalR3 (4), regulates homeostatic and motivated behaviors including pain perception, sleep, food intake, sexual activity, learning, and memory (5). Galaninergic transmission modulates the activity of monoaminergic neurons in the ventral tegmental area, DRN, and locus coeruleus (LC) (6-10). Galanin receptor subtypes GalR1 (7) and GalR2 are expressed in DRN neurons (11) that can be activated by galanin dendritically released from the dorsal raphe 5-HT neurons (9, 12) or from surrounding galanin immunoreactive terminals (7). In the noradrenergic nucleus LC, an area that is closely connected both structurally and functionally to DRN (13,14), GalR1 expression is induced by morphine withdrawal (15), and the galanin receptor agonist, galnon, was shown to attenuate several withdrawal signs (16). It is worth noting that drug withdrawal often precipitates symptoms of depression, and depression is a ...

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“…Galanin actions are mediated through three G proteincoupled receptors present in the brain and the peripheral nervous system (4)(5)(6). Transgenic mice overexpressing galanin have much higher seizure thresholds (7), and the galanin receptor 1 (GalR1) Ϫ/Ϫ mice have spontaneous seizures, demonstrating the role of galanin and its receptor in seizure control (8).…”

mentioning

confidence: 99%

Galmic, a nonpeptide galanin receptor agonist, affects behaviors in seizure, pain, and forced-swim tests

Bartfai

Lü

Badie-Mahdavi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

134

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The pharmacological exploitation of the galanin receptors as drug targets for treatment of epilepsy, depression, and pain has been hampered by the lack of workable compounds for medicinal chemists from random screening of large chemical libraries. The present work uses the tripeptidomimetic galnon and displays its presumed pharmacophores on a rigid molecular scaffold. The scaffold is related to marine natural products and presents three functional groups near one another in space, in a manner reminiscent of a protein surface. An active compound, Galmic, was identified from a small synthetic library and tested in vitro and in vivo for its affinity and efficacy at galanin receptors. Galmic has micromolar affinity for GalR1 receptors (K i ‫؍‬ 34.2 M) and virtually no affinity for GalR2 receptors. In vitro, Galmic, like galanin, suppresses long-term potentiation in the dentate gyrus; it blocks status epilepticus when injected intrahippocampally or administered i.p. Galmic applied i.p. shows antidepressant-like effects in the forced-swim test, and it is a potent inhibitor of flinching behavior in the inflammatory pain model induced by formalin injection. These data further implicate brain and spinal cord galanin receptors as drug targets and provide an example of a systemically active compound based on a scaffold that mimics protein surfaces.G alanin, a 29-to 30-aa-long neuropeptide, has been shown to affect feeding, cognitive, and sexual behavior and to regulate seizure and pain thresholds when applied intraventricularly (1-3). Galanin actions are mediated through three G proteincoupled receptors present in the brain and the peripheral nervous system (4-6). Transgenic mice overexpressing galanin have much higher seizure thresholds (7), and the galanin receptor 1 (GalR1) Ϫ/Ϫ mice have spontaneous seizures, demonstrating the role of galanin and its receptor in seizure control (8). Despite the wealth of biological information on galanin signaling, no progress has been made in using the galanin-receptor subtypes as drug targets. The lack of progress is largely due to the poor results from random screening at several major pharmaceutical companies (9). More than 4 million compounds were screened, but no workable compounds for medicinal chemical optimization were identified. Both Johnson & Johnson (10) and Schering have published reports of compounds active at high micromolar concentrations that had stability problems, as well as other problems (9). The only nonpeptide galanin receptor ligand available is galnon, a substance intended to display analogs of the three major pharmacophores of galanin, Trp-2, Asn-5, and Tyr-9 (11, 12), on a linear, peptide-like backbone. Galnon is a lowaffinity, nonreceptor-subtype-selective agonist that acts at both GalR1-and GalR2-type receptors (13). Despite its serious shortcomings, galnon, within a year of its synthesis, was shown to affect behavioral symptoms and neurochemical correlates in opiate withdrawal (14), pain (15), and seizure (13) The present work describes the synthesis and ...

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The human galanin receptor: ligand-binding and functional characteristics in the Bowes melanoma cell line

Cited by 55 publications

References 29 publications

β-Amyloid1–42 Binds to α7 Nicotinic Acetylcholine Receptor with High Affinity

β-Amyloid1–42 Binds to α7 Nicotinic Acetylcholine Receptor with High Affinity

A role for galanin in antidepressant actions with a focus on the dorsal raphe nucleus

Galmic, a nonpeptide galanin receptor agonist, affects behaviors in seizure, pain, and forced-swim tests

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