1.Regulation of kindling epileptogenesis by hippocampal galanin type 1 and type 2 receptors: The effects of subtype-selective agonists and the role of G-protein-mediated signaling.
Mazarati A;Lundström L;Sollenberg U;Shin D;Langel U;Sankar R J Pharmacol Exp Ther. 2006 Aug;318(2):700-8. Epub 2006 May 12.
The search for antiepileptic drugs that are capable of blocking the progression of epilepsy (epileptogenesis) is an important problem of translational epilepsy research. The neuropeptide galanin effectively suppresses acute seizures. We examined the ability of hippocampal galanin receptor type 1 (GalR1) and type 2 (GalR2) to inhibit kindling epileptogenesis and studied signaling cascades that mediate their effects. Wistar rats received 24-h-long intrahippocampal infusion of a GalR1/2 agonist galanin(1-29), GalR1 agonist M617 [galanin(1-13)-Gln14-bradykinin(2-9)-amide], or GalR2 agonist galanin(2-11). The peptides were administered alone or combined with an inhibitor of Gi protein pertussis toxin (PTX), Gi-protein activated K+ channels (GIRK) inhibitor tertiapin Q (TPQ), G(q/11) protein inhibitor [D-Arg1,D-Trp(5,7,9),Leu11]-substance P (dSP), or an inhibitor of intracellular Ca2+ release dantrolene. Sixteen hours into drug delivery, the animals were subjected to rapid kindling-60 electrical trains administered to ventral hippocampus every 5 min. M617 delayed epileptogenesis, whereas galanin(1-29) and galanin(2-11) completely prevented the occurrence of full kindled seizures. TPQ abolished anticonvulsant effect of M617 but not of galanin(2-11).
2.Mechanisms of antinociception of spinal galanin: how does galanin inhibit spinal sensitization?
Hua XY;Salgado KF;Gu G;Fitzsimmons B;Kondo I;Bartfai T;Yaksh TL Neuropeptides. 2005 Jun;39(3):211-6. Epub 2005 Mar 19.
Galanin by a spinal action has been shown to have an antihyperalgesic action. Thus, in rats with lumbar intrathecal (IT) catheters, the thermal hyperalgesia evoked by carrageenan paw injection was blocked by IT delivery of galanin(1-29) (Gal(1-29)) and galanin(2-11) (Gal(2-11)) with the rank order of activity being Gal(1-29)>Gal(2-11). We sought to determine whether this spinal action reflects an effect upon afferent transmitter release, e.g., substance P (SP), and/or on secondary neurons, e.g., signaling postsynaptic to neurokinin 1 (NK1) receptor activation. To address the question on afferent release, we investigated the effect of IT administration of galanin on tissue injury-induced spinal NK1 internalization (an indicator of SP release). Noxious stimulation (paw compression) produced an increase in NK1 internalization in dorsal horn lamina I. IT pretreatment of rats with Gal(1-29) and Gal(2-11) significantly attenuated the evoked NK1 internalization, with the rank order of activity being Gal(1-29)>Gal(2-11)>saline. To address the question of postsynaptic action, we examined the effects of IT galanin upon IT SP-induced thermal hyperalgesia and spinal PGE2 release. Application of SP (30 nmol) directly to spinal cord led to a decrease in thermal thresholds and a profound increase in PGE(2) concentration in spinal dialysates.
3.Important pharmacophores for binding to galanin receptor 2.
Lundström L;Lu X;Langel U;Bartfai T Neuropeptides. 2005 Jun;39(3):169-71. Epub 2005 Feb 16.
Galanin(2-11) has been introduced as a receptor subtype selective ligand for the GalR2 subtype of the galanin receptors, and has gained use in pharmacological studies of galaninergic signaling in the past two years. By introducing l-Ala substitutions in the galanin(2-11) sequence, we have examined the amino acid residues which are of importance for binding to the GalR2 receptor. Our study shows that Trp2, Asn5, Gly8 and Tyr9 are of great importance for high affinity binding. When placed in an alpha-helical conformation, the side chains of these residues are, with the exception of Tyr9, displayed on the same "side" of the peptide. This information is useful in the rational design of non-peptide type GalR2 receptor ligands.
