Galanin, galanin receptor subtypes and depression-like behaviour.

The pathophysiology of depression remains unclear, but involves disturbances in brain monoaminergic transmission. Current antidepressant drugs, which act by enhancing this type of neurotransmission, have limited therapeutic efficacy in a number of patients, and also cause serious side-effects, which limits their compliance. Increasing evidence suggests that neuropeptides, including galanin, can be of relevance in mood disorders. Galanin is co-expressed with and modulates noradrenaline and serotonin transmission, both implicated in depression. Pharmacological and genetic studies suggest a role for galanin in depression-like behaviour in rodents, involving specific receptor subtypes. Thus, stimulation of GalR1 and/or GalR3 receptors results in depression-like phenotype, while activation of the GalR2 receptor reduces depression-like behaviour in the rat. These findings suggest that galanin receptor subtypes may represent novel targets for the development of antidepressant drugs.

Differential role of galanin receptors in the regulation of depression-like behavior and monoamine/stress-related genes at the cell body level.

The present study on rat examined the role of galanin receptor subtypes in regulation of depression-like behavior as well as potential molecular mechanisms involved in the locus coeruleus (LC) and dorsal raphe (DR). The effect of intracerebroventricular (i.c.v.) infusion of galanin or galanin receptor GalR1- and GalR2-selective ligands was studied in the forced swim test, followed by quantitative in situ hybridization studies. Naive control, non-treated (swim control), saline- and fluoxetine-treated rats were used as controls in the behavioral and in situ hybridization studies. Subchronic treatment with fluoxetine reduced immobility and climbing time. Intracerebroventricular infusion of galanin, the GalR1 agonist M617 or the GalR2 antagonist M871 increased, while the GalR2(R3) agonist AR-M1896 decreased, immobility time compared to the aCSF-treated animals. Galanin also decreased the time of climbing. Galanin mRNA levels were upregulated by the combination of injection+swim stress in the saline- and the fluoxetine-treated groups in the LC, but not in the DR. Also tyrosine hydroxylase levels in the LC were increased following injection+swim stress in the saline- and fluoxetine-treated rats. Tryptophan hydroxylase 2 and serotonin transporter mRNAs were not significantly affected by any treatment. 5-HT(1A) mRNA levels were downregulated following i.c.v. galanin, M617 or AR-M1896 infusion. These results indicate a differential role of galanin receptor subtypes in depression-like behavior in rodents: GalR1 subtype may mediate 'prodepressive' and GalR2 'antidepressant' effects of galanin. Galanin has a role in behavioral adaptation to stressful events involving changes of molecules important for noradrenaline and/or serotonin transmission.

Electrostatic domino effect in the Shaker K channel turret.

Voltage-gated K channels are regulated by extracellular divalent cations such as Mg(2+) and Sr(2+), either by screening of fixed negative surface charges, by binding directly or close to the voltage sensor, or by binding to the pore. Different K channels display different sensitivity to divalent cations. For instance, 20 mM MgCl(2) shifts the conductance versus voltage curve, G(V), of the Kv1-type Shaker channel with 14 mV, while the G(V) of Kv2.1 is shifted only with 7 mV. This shift difference is paralleled with different working ranges. Kv1-type channels open at approximately -20 mV and Kv2.1 channel open at approximately +5 mV. The aim of this study was to identify critical residues for this Mg(2+)-induced G(V) shift by introducing Kv2.1 channel residues in the Shaker K channel. The K channels were expressed in Xenopus laevis oocytes and studied with the two-electrode voltage-clamp technique. We found that three neutral-to-positive amino-acid residue exchanges in the extracellular loops connecting transmembrane segments S5 and S6 transferred the Mg(2+)-shifting properties. The contributions of the three residues were additive, and thus independent of each other, with the contributions in the order 425 > 419 > 451. Charging 425 and 419 not only affect the Mg(2+)-induced G(V) shift with 5-6 mV, but also shifts the G(V) with 17 mV. Thus, a few strategically placed surface charges clearly modulate the channel's working range. Residue 425, located at some distance away from the voltage sensor, was shown to electrostatically affect residue K427, which in turn affects the voltage sensor S4-thus, an electrostatic domino effect.

Galanin enhances and a galanin antagonist attenuates depression-like behaviour in the rat.

The effect of intracerebroventricular infusion of galanin and/or the galanin antagonist M35 was studied in the forced swim test. Animals were pre-exposed to water for 15 min 24 h prior to test. Immobility and climbing were assessed during the second, 5 min exposure to water. Rats receiving a single infusion of galanin (3 nmol) displayed a significant increase of immobility. This effect was blocked by co-administration of M35 (1 nmol). M35 alone (1 nmol) produced a significant decrease of immobility. The results further support the hypothesis that galanin may play a role in mood disorders, and that galanin antagonists may represent new candidates for antidepressant treatment.