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  • 1. Anderson, Maria E.
    et al.
    Runesson, Johan
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Saar, Indrek
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Robinson, John K.
    Galanin, through GalR1 but not GalR2 receptors, decreases motivation at times of high appetitive behavior2013In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 239, p. 90-93Article in journal (Refereed)
    Abstract [en]

    Galanin is a 29/30-amino acid long neuropeptide that has been implicated in many physiological and behavioral functions. Previous research has shown that i.c.v. administration of galanin strongly stimulates food intake in sated rats when food is freely available, but fails to stimulate this consumption when an operant response requirement is present. Using fixed ratio (FR) schedules, we sought to further clarify galanin's role in motivated behavior by administering galanin i.c.v. to rats working on fixed ratio schedules requiring either a low work condition (FR1) or higher work conditions (FR > 1) to obtain a 0.2% saccharin reward. Rats in the FR > 1 group were assigned to either an FR3, FR5 or FR7 schedule of reinforcement. The rate of reinforcement decreased for only the FR > 1 group as compared to saline controls. Furthermore, injections of GalR1 receptor agonist M617 led to a similar, marginally significant decrease in the number of reinforcers received in the FR > 1 condition, but a decrease was not seen after injections of GalR2 receptor agonist M1153. Taken together, these results show that galanin may be playing a role in decreasing motivation at times of high appetitive behavior, and that this effect is likely mediated by the GalR1 receptor.

  • 2. Groves-Chapman, Jessica L.
    et al.
    Runesson, Johan
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Holmes, Philip V.
    Galanin receptor agonists protect against kainic acid-induced excitotoxicity in the rat hippocampus2011Conference paper (Refereed)
    Abstract [en]

    Galanin is a peptide neurotransmitter with neuroprotective actions. Administration of galanin or selective galanin receptor agonists to rats reduces convulsant-induced seizure behavior. However, it remains unclear whether galanin exerts a neuroprotective effect in vivo and which galanin receptor subtype may mediate this effect. The present experiments evaluated the impact of two separate galanin receptor agonists, M1145 and M1154, which are specific for GAL R2 and GAL R1/R2 respectively, on seizure behavior and neuronal excitotoxicity following intracerebroventricular (ICV) administration of kainic acid. Male, Sprague-Dawley rats received ICV infusions of M1145, M1154, or saline prior to an ICV infusion of kainic acid. Seizure behaviors were rated for 30 minutes post-infusion, and rats were euthanized and transcardially perfused 48 hours later. Twenty micron coronal sections of the hippocampal region were obtained and nissl-stained for microscopic cell counting of pyramidal neurons in the CA3 region.Neither galanin receptor agonist reduced the seizure behaviors induced by kainic acid. Cell counting in CA3 revealed that kainic acid treatment alone caused near complete destruction of cells. However, rats pretreated with the galanin receptor agonists showed reduced cell loss. These results provide further evidence of the protective role of galanin in the hippocampus and suggest that the GAL R2 receptor mediates these effects.

  • 3.
    Gustafsson, Helena
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Runesson, Johan
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lindegren, Heléne
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Axelsson, Viktoria
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    The use of the human neuroblastoma SH-SY5Y cell line for estimation of acute systemic toxicity in vitro.2007Conference paper (Refereed)
    Abstract [en]

    Acute systemic toxicity, expressed as human lethal blood peak concentration or the dose inducing 50 % lethality in an animal population (LD50), can be estimated by general cytotoxicity tests using proliferating mammalian cell lines for 70-80 % of all chemicals. The cytotoxicity for the remaining chemicals over or under estimate the LD50 values/human lethal blood peak concentrations because of their very specific molecular targets or toxicokinetic features in vivo. The objective of the EU funded integrated project “ACuteTox” is to develop a strategy in which organ-specific endpoints and toxicokinetic features are taken into consideration in the in vitro prediction of acute systemic toxicity. The human neurotblastoma SH-SY5Y cell line was used as a model for studies on neurospecific targets, which are know to be crucial for survival. All endpoints were investigated after short exposure times (minutes to an hour) at concentrations of the test chemicals that did not affect the cell viability, measured as cell membrane leakage of lactate dehydrogenase. The effects of 23-26 compounds (drugs, pesticides and industrial chemicals) were studied on the cell membrane potential (CMP), voltage dependent Ca2+ channels (VDCC), muscarinic acetylcholine receptor (mAChR) function, acetylcholinesterase (AChE) activity and noradrenalin uptake. The results showed that the CMP was altered by atropine, amphetamine, mercury chloride, methadone, nicotine, pentachlorphenol, sodium lauryl sulphate (SLS) and verapamil, where as an effect on VDCC could be detected for amphetamine, atropine, colchicine, pentachlorphenol, SLS and verapamil. The mAChR function was measured as carbachol-induced Ca2+, i.e. activation of phospholipase C. Amphetamine, pentachlorphenol, SDS and verapamil attenuated the carbachol response by 50% at concentrations about 1 mM, but the specific mAChR antagonist atropine had the same effect at 3 nM. Nicotine, caffeine, pentachlorphenol, methadone, mercury chloride, SLS and the specific inhibitors physostigmine, dichlorvos and malathion attenuated the AChE activity at significantly non-cytotoxic concentrations in SH-SY5Y cells after 60 minutes of exposure. Parathion did not inhibit the AChE activity after 60 minutes exposure, but after 48 hr, indicating that oxidation of parathion to the active inhibitor paraoxon took place in the cell culture. This phenomenon was also observed for malathion, which displayed a lower EC50 value after the prolonged exposure time. The noradrenalin uptake was affected by atropine, caffeine, carbamazepine, amphetamine, diazepam, isopropanol, methadone, SLS and verapamil. A comparison of the active concentrations with the basal cytotoxicity measured as neutral red uptake in mouse fibroblast 3T3 cells indicated that the AChE assay is useful for detection of AChE inhibitors and possibly also AChR ligands. The VDCC endpoint was useful as an alert only for verapamil and the mAChR function was only specifically affected by atropine. The noradrenalin uptake indicated a clear alert for amphetamine and methadone, which was expected, but not for the other test compounds. These results indicate that the usefulness of these endpoints in a general test battery for estimation of acute systemic toxicity is limited, except for AChE activity measurements. However, the results clearly showed that the compounds with known mechanisms (e.g. atropine, verapamil, amphetamine and methodone ) displayed expected effects on their specific endpoints.

  • 4.
    Gustafsson, Helena
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Runesson, Johan
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lundqvist, Jessica
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lindegren, Heléne
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Axelsson, Viktoria
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Neurofunctional endpoints assessed in human neuroblastoma SH-SY5Y cells for estimation of acute systemic toxicity2010In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 245, no 2, p. 191-202Article in journal (Refereed)
    Abstract [en]

    The objective of the EU-funded integrated project ACuteTox is to develop a strategy in which general cytotoxicity, together with organ-specific toxicity and biokinetic features, are used for the estimation of human acute systemic toxicity. Our role in the project is to characterise the effect of reference chemicals with regard to neurotoxicity. We studied cell membrane potential (CMP), noradrenalin (NA) uptake, acetylcholine esterase (AChE) activity, acetylcholine receptor (AChR) signalling and voltage-operated calcium channel (VOCC) function in human neuroblastoma SH-SY5Y cells after exposure to 23 pharmaceuticals, pesticides or industrial chemicals. Neurotoxic alert chemicals were identified by comparing the obtained data with cytotoxicity data from the neutral red uptake assay in 3T3 mouse fibroblasts. Furthermore, neurotoxic concentrations were correlated with estimated human lethal blood concentrations (LC50). The CMP assay was the most sensitive assay, identifying eight chemicals as neurotoxic alerts and improving the LC50 correlation for nicotine, lindane, atropine and methadone. The NA uptake assay identified five neurotoxic alert chemicals and improved the LC50 correlation for atropine, diazepam, verapamil and methadone. The AChE, AChR and VOCC assays showed limited potential for detection of acute toxicity. The CMP assay was further evaluated by testing 36 additional reference chemicals. Five neurotoxic alert chemicals were generated and orphendrine and amitriptyline showed improved LC50 correlation. Due to the high sensitivity and the simplicity of the test protocol, the CMP assay constitutes a good candidate assay to be included in an in vitro test strategy for prediction of acute systemic toxicity.

  • 5.
    Runesson, Johan
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Delineating Ligand-Receptor Interactions and the Design of Subtype Selective Galanin Receptor Ligands2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    We now celebrate that it is 30 years since galanin was first isolated. During these three decades galanin has been identified in numerous tissues and physiological processes, and in an abundant number of species. In the nervous system galanin primarily displays a modulatory role. The galaninergic system consists of a number of bioactive peptides with a highlyplastic expression pattern and three different receptors, GalR1-GalR3. The lack of receptor subtype selective ligands and antibodies have severely hampered the characterization of this system. Therefore, most of the knowledgehas been drawn from experiments with transgenic animals, which has givensome major conclusions, despite the risk of inducing compensatory effects inthese animal studies. Therefore, the production of subtype selective ligandsis of great importance to delineate the galanin system and slowly experimental data from receptor subtype selective ligand trials is emerging. This thesis aims at studying galanin receptor-ligand interactions and to increase and improve the utilized tools in the galanin research field, especially the development of novel galanin receptor subtype selective ligands. Paper I demonstrates the potential to N-terminally extend galanin analogues and the successful development of a GalR2 selective ligand. In addition, a cell line stably expressing GalR3 was developed to improve and simplify future evaluations of receptor subtype selective galanin ligands. Paper II extends the number of GalR2 selective ligands and shows that i.c.v. administration of galanin receptor ligands stimulates food intake through GalR1. Paper III demonstrates the successful development of a mixed GalR1/GalR2 agonist without any detectable interaction with GalR3. Subsequently, this peptide was used to delineate which receptor subtype mediatesthe neuroprotective effects of galanin in the CA3 region of hippocampus. Furthermore, a robust protocol for detection of receptor activation was developed to ease the detection of the relative potency of novel ligands at the three galanin receptor subtypes. Paper IV describes the finding of several essential amino acids for ligand interaction in GalR3 through the performance of an L-alanine mutagenesis study. A constructed in silico homology model of GalR3 confirmed and extended these findings. In conclusion, this thesis provides a novel design strategy for galanin receptor ligands and increases the understanding of ligand interactions with the GalR3. Furthermore, published ligands together with new galanin analogues have proven to be highly receptor specific, thus implicating that a future delineation of the galaninergic system as a therapeutic target is possible.

  • 6.
    Runesson, Johan
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Galanin receptor ligands2009Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    In the nervous system galanin primarily displays a modulatory role. The galaninergic system consists of a number of bioactive peptides with a highly plastic expression pattern and three different receptors. The lack of receptor subtype selective ligands and antibodies have severely hampered the charac-terization of this system. Therefore, most of the knowledge has been drawn from experiments with transgenic animals, which has given some major conclusions, despite the compensatory effects seen in several animal studies. Therefore, the production of subtype selective ligands is of great importance to delineate the galanin system and slowly experimental data from receptor subtype selective ligand trials is emerging.

    This thesis aims at studying galanin receptor-ligand interactions and to increase and improve the utilized tools in the galanin research field, espe-cially the development of novel galanin receptor subtype selective ligands. Paper I demonstrates the potential to N-terminally extend galanin ana-logues and the successful development of a galanin receptor 2 (GalR2) selec-tive ligand. In addition, a cell line stably expressing galanin receptor 3 (GalR3) was developed, to improve and simplify future evaluations of sub-type selective galanin ligands. Paper II measures the affinities of M617 and M871 to GalR3 and demon-strates that M871 preferentially binds GalR2. Furthermore, the relatively high affinity of M617 was evaluated by assessing the contribution in recep-tor interaction of individual amino acid residues in the C-terminal part of the M617.

    In conclusion, this thesis has provided a novel design strategy for galanin receptor ligands and increased the understanding of ligand interactions with the GalR3. Furthermore, M1145 has together with new analogues proven to be highly GalR2 specific, holding promises to future delineation of the galaninergic system as a therapeutic target.

  • 7.
    Runesson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Groves-Chapman, Jessica L.
    Karlsson, Kristin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Saar, Indrek
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Sillard, Rannar
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Holmes, Philip V.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Pharmacological stimulation of galanin receptor 1 but not galanin receptor 2 attenuates kainic acid-induced neuronal cell death in the rat hippocampusManuscript (preprint) (Other academic)
    Abstract [en]

    The neuropeptide galanin is widely distributed in the central and peripheral nervous systems. Galanin is part of a bigger family of bioactive peptides and its biological activity is mediated through three G-protein coupled receptor subtypes, GalR1-3. The last 20 years have provided data supporting a neuroprotective effect of galanin that probably is mediated through the activation of GalR1 and GalR2.

    In this study, an additional galanin receptor ligand, M1154, was developed to fully address the pharmaceutical potential of galanin receptor subtype selective ligands to inhibit excitotoxic cell death. We thereafter adapted a single protocol for signaling assay for all three galanin receptors, by utilizing a non-labeled real time instrument, to ease classification of novel ligands according to their ability to activate the different galanin receptor subtypes. M1154 is a GalR1/2 selective ligand in our binding and signaling assays with no detectable interaction with GalR3.

    The novel M1154 peptide was compared to earlier published selective ligands, namely M617 and M1145, in its ability to reduce the excitotoxic effects of kainic acid (KA). While no significant difference in the time course or severity of induced seizure activity was observed, administration of either M617 or M1154 before KA administration, significantly attenuated the neuronal cell death in the hippocampus. Our results clearly show the potential therapeutic value of agonists selective for GalR1 as neuroprotective agents for the prevention of excitotoxic neuronal cell death.

  • 8.
    Runesson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Karlsson, Kristin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    A galanin(2-11) analogue specific for GalR22011Conference paper (Other academic)
    Abstract [en]

    The neuropeptide galanin family currently consists of four members, namely galanin, galanin-message-associated peptide (GMAP), galanin-like peptide (GALP) and alarin. Galanin has been shown to influence several physiological processes including cognition, affective behavior, nerve injury, Alzheimer’s disease, neuroregeneration, seizures, feeding, and hormone release. The co-localization with other neuromodulators and the distinct up-regulation during and after pathological disturbances has drawn attention to this neuropeptide family. The regionally specific expression of the galanin receptors (GalR1-3) suggests different physiological roles, a feature which mostly remains unexplored due to the lack of stable, selective and potent ligands acting on the galanin receptor subtypes.

    The introduction of galanin(2-11) as a GalR2 selective ligand was an important advance in the galanin field. Unfortunately, later publications described that galanin(2-11) also binds with similar affinity to GalR3, a critical limitation when delineating the interplay between galanin receptor subtypes. Even so, galanin(2-11) has been given extensive attention and been used in numerous study as a non-GalR1 ligand. We now introduce an analogue of galanin(2-11) that combines the GalR2 selective binding, comparable with the published M1145 with the small size of galanin(2-11). Utilizing this true GalR2 selective ligand will help to define the role GalR2 in general and especially for already published studies that has been exploit galanin(2-11).

  • 9.
    Runesson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Receptor subtype selective galanin analogous for better understanding of the role of galanin in cancer progression2010Conference paper (Other academic)
    Abstract [en]

    Galanin and galanin receptors have been found in several tumors. Galanin signaling has been studied in more detail in small cell lung carcinoma, where signaling via the GalR2 decreases the tumor growth. Galanin has also been included in a clinical therapy for pancreatic tumor together with a somatostatin agonist and serotonin. However, galanin signals via three receptors subtype with a broad expression pattern. We have therefore, developed several subtype selective galanin analogous that should reduce the side effects caused by galanin treatment. Therefore, we hope that the successful design of galanin receptor subtype selective ligands increase the interest for galanin and cancer progression.

  • 10.
    Runesson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Robinson, John K.
    Eriksson Sollenberg, Ulla
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Twenty-Five Years of Galanin Research2009In: Bioactive Peptides / [ed] John Howl, Sarah Jones, Boca Raton: CRC Press, 2009, p. 237-260Chapter in book (Refereed)
  • 11.
    Runesson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Saar, Indrek
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Järv, Jaak
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Novel peptide agonists, favoring galanin receptor type 2 over galanin receptor type 1 and 32009In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 276, p. 164-164Article in journal (Refereed)
    Abstract [en]

    The galanin peptide family and its three receptors have with compelling evidence been implicated in a variety of human disorders. The co-localization with other neuromodulators and the distinct up-regulation during and after pathological disturbances has drawn attention to this neuropeptide family although, so far, no therapeutics have emerged past the animal model stage. In the current study we present data on receptor binding and functional response from novel galanin receptor type 2 (GalR2) selective chimeric peptides, including the M1145 peptide which show more than 90-fold higher affinity for galanin receptor type 2 over galanin receptor type 1 and a 76-fold higher affinity over galanin receptor type 3. Furthermore, the peptide produces an agonistic effect in vitro seen as an increase in inositol phosphate (IP) accumulation, both in the absence or the presence of galanin. The peptide design with a N-terminal extension of galanin(2-13), prevails new insights in the assembly of novel subtype specific ligands for the galanin receptor family. Preliminary data on peptides further exploring the usage of N-terminal extension shows even higher preferentiality towards the GalR2 and opens new possibilities to clarify the galanin system as a putative drug target.

  • 12.
    Runesson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Saar, Indrek
    University of Tartu.
    Karlsson, Kristin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Kurrikoff, Kaido
    University of Tartu.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    The quest for a GPCR subtype selective ligand for the galanin system: development and utilization2012Conference paper (Other academic)
    Abstract [en]

    The family of GPCR’s has for long served as the most common pharmaceutical drug target. Even so, some receptors have failed to show potent interactions when exposed to big screenings libraries in the past. Three of these receptors are the so called galanin receptors (GalR).

    Galanin is a neuroendocrine peptide that is widely distributed in both the CNS and PNS, as well as in the endocrine system. Galanin has been shown to influence several physiological processes including cognition, affective behavior, nerve injury, Alzheimer’s disease, neuroregeneration, seizures, feeding, and hormone release. The regionally specific expression of the galanin receptors (GalR1-3) suggests different physiological roles, a feature which mostly remains unexplored due to the lack of selective ligands acting on the GalR subtypes. The galanin research field has until very recently been struggling with the limitation of having neither receptor subtype specific ligands nor antibodies. Recently, we and others have successfully developed pharmacological tools for the galanin research field, including allosteric modulators, BBB-penetrating ligands and receptor subtype specific ligand.

    We here present several promising ligands that are GalR subtype selective [Runesson 2009, Saar 2011, several manuscripts in preparations] and these might be future candidates to unravel the function of GalR subtypes. The goal of this poster will be to present our latest tools and some results from animal studies with models related to depression, seizures and feeding. We find these new developments of pivotal interest for the galanin research field and hope that this neuropeptide will now be revived and that new and old findings could be translated into the clinical setting.

  • 13.
    Runesson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Saar, Indrek
    Karlsson, Kristin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Sillard, Rannar
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    The quest for a GPCR selective ligand – a bottleneck2011Conference paper (Other academic)
    Abstract [en]

    The family of GPCR’s has for long served as the most common pharmaceutical drug target. Even so, some receptors have failed to show any interactions when exposed to big screenings libraries in the past and consequently they also lack potent small molecules acting as ligands on these different receptors. Three of these receptors are the so called galanin receptors (GalR).

    Galanin is a neuroendocrine peptide that is widely distributed in both the central and peripheral nervous systems as well as in the endocrine system. The galanin peptide family currently consists of four members, namely galanin, galanin-message-associated peptide (GMAP), galanin-like peptide (GALP) and alarin. Galanin has been shown to influence several physiological processes including cognition, affective behavior, nerve injury, Alzheimer’s disease, neuroregeneration, seizures, feeding, and hormone release. The co-localization with other neuromodulators and the distinct up-regulation during and after pathological disturbances has drawn attention to this peptide family. The regionally specific expression of the galanin receptors (GalR1-3) suggests different physiological roles, a feature which mostly remains unexplored due to the lack of selective ligands acting on the galanin receptor subtypes.

    The first introduced receptor subtype specific ligand in the field was galanin(2-11) as a GalR2 selective ligand, which was an important advance in the galanin field. Unfortunately, later publications described that galanin(2-11) also binds with similar affinity to GalR3, a critical limitation when delineating the interplay between galanin receptor subtypes. Even so, galanin(2-11) has been given extensive attention and been used in numerous study as a non-GalR1 ligand.

    We here present several promising ligands that are GalR subtype selective and these might be future candidates to unravel the function of GalR subtypes. We are currently testing their signalling in order to find novel agonists/antagonists for each receptor, and prepare to test them in relevant biological systems.

  • 14.
    Runesson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Saar, Indrek
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Lundström, Linda
    Järv, Jaak
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    A novel GalR2-specific peptide agonist2009In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 43, no 3, p. 187-192Article in journal (Refereed)
    Abstract [en]

    The galanin peptide family and its three receptors have with compelling evidence been implicated in several high-order physiological disorders. The co-localization with other neuromodulators and the distinct up-regulation during and after pathological disturbances has drawn attention to this neuropeptide family. In the current study we present data on receptor binding and functional response for a novel galanin receptor type 2 (GalR2) selective chimeric peptide, M1145 [(RG)(2)-N-galanin(2-13)-VL-(P)(3)-(AL)(2)-A-amide]. The M1145 peptide shows more than 90-fold higher affinity for GalR2 over GalR1 and a 76-fold higher affinity over GalR3. Furthermore, the peptide yields an agonistic effect in vitro, seen as an increase in inositol phosphate (IP) accumulation, both in the absence or the presence of galanin. The peptide design with a N-terminal extension of galanin(2-13), prevails new insights in the assembly of novel subtype specific ligands for the galanin receptor family and opens new possibilities to apply the galanin system as a putative drug target.

  • 15.
    Runesson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Saar, Indrek
    Sillard, Rannar
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    M1154 – A novel galanin ligand to delineate the galaninergic system2010In: Peptides 2010: Proceedings of the European Peptide Symposium / [ed] Michal Lebl, Morten Meldal, Knud J. Jensen, Thomas Høeg-Jensen, European Peptide Society and PSP , 2010Conference paper (Other academic)
    Abstract [en]

    The galanin family currently consists of four members, namely galanin, galanin-message-associated peptide (GMAP), galanin-like peptide (GALP) and alarin. The galanin peptide family and its three receptors (GalR1-3) have with compelling evidence been implicated in a variety of human disorders. The co-localization with other neuromodulators and the distinct up-regulation during and after pathological disturbances has drawn attention to this neuropeptide family. Here we present data on receptor binding and preliminary data in functional response for the novel M1154 peptide, including a comparison with several GalR2 selective peptides. M1154 retains high affinity binding to GalR1 and GalR2 although it has no detectable binding to GalR3. We believe that utilizing this selective galanin ligand together with previous published M1145 raise the possibility to delineate the galanin system.

     

  • 16.
    Runesson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Saar, Indrek
    Sillard, Rannar
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. Tartu University, Estonia.
    Receptor ligands to delineate the galaninergic system2010In: FENS Abstracts, Federation of European Neuroscience Societies , 2010, Vol. 5, p. 104.19-Conference paper (Refereed)
    Abstract [en]

    The galanin family currently consists of four members, namely galanin, galanin-message-associated peptide (GMAP), galanin-like peptide (GALP) and alarin. The galanin peptide family and its three receptors have with compelling evidence been implicated in a variety of human disorders. The co-localization with other neuromodulators and the distinct up-regulation during and after pathological disturbances has drawn attention to this neuropeptide family. Here we present data on receptorbinding and preliminary data in functional response for several novel galanin receptor selective peptides, including a comparison with the published M1145 peptide. The design strategy with a N-terminal extension of galanin(2-13) in M1145 peptide, prevailed new insights in the assembly of novel subtype specific ligands for the galanin receptor family. Modification of the M1145 sequence led to the design of M1162, with an improved GalR2 selectivity. Furthermore, with a new design strategy, the peptide M1154 was produced, which retains high affinity binding to GalR1 and GalR2 although it has no detectable binding to GalR3. In conclusion, we have succeeded in the production of a new generation of subtype selective galanin ligands that raise the possibility to delineate the galanin system and determine if the galaninergic system is a putative drug target.

  • 17.
    Runesson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Sollenberg, Ulla E.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Jurkowski, Wiktor
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Yazdi, Samira
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Eriksson, Einar E.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Determining receptor–ligand interaction of human galanin receptor type 32010In: Neurochemistry International, ISSN 0197-0186, E-ISSN 1872-9754, Vol. 57, no 7, p. 804-811Article in journal (Refereed)
    Abstract [en]

    Galanin is a neuropeptide found throughout the central and peripheral nervous systems of a wide range of species, ranging from human and mouse to frog and tuna. Galanin mediates its physiological roles through three receptors (GalR1–3), all members of the G-protein coupled receptor family. In mapping these roles, receptor subtype selective ligands are crucial tools. To facilitate the ligand design, data on receptor structure and interaction points are of great importance. The current study investigates the mechanism by which galanin interacts with GalR3. Mutated receptors were tested with competitive binding analysis in vitro. Our studies identify six mutagenic constructs that lost receptor affinity completely, despite being expressed at the cell surface. Mutations of the Tyr1033.33 in transmembrane helix (TM) III, His2516.51 in TM VI, Arg2737.35 or His2777.39 in TM VII, Phe2636.63 or Tyr2707.32 in the extracellular loop III all result in complete reduction of ligand binding. In addition, docking studies of an in silico model of GalR3 propose that four of the identified residues interact with pharmacophores situated within the galanin(2–6) sequence. This study provides novel insights into the interaction between ligands and GalR3 and highlights the requirement for correct design of targeting ligands.

  • 18.
    Runesson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Sollenberg, Ulla E.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Identification of important pharmacophores in the galanin receptor subtypes2010Conference paper (Other academic)
    Abstract [en]

    The neuropeptide galanin family currently consists of four members, namely galanin, galanin-message-associated peptide (GMAP), galanin-like peptide (GALP) and alarin. Galanin has been shown to influence several physiological processes including cognition, affective behavior, nerve injury, Alzheimer’s disease, neuroregeneration, seizures, feeding, and hormone release. Galanin and galanin receptors (GalR1-3) show a widespread distribution throughout nervous systems where galanin co-localizes with several neuropeptides and/or classical neurotransmitters. Regionally specific expression of the galanin receptors suggests different physiological roles, a feature which mostly remains unexplored due to the lack of stable, selective and potent ligands acting on the galanin receptor subtypes. In order to design novel galanin receptor ligands with enhanced subtype selectivity we are aiming at determining the molecular interaction between the galanin peptide and the galanin receptor subtypes. By introducing site directed mutations to the extracellular loops and the external parts of the transmembrane domains in the galanin receptor subtypes we will characterize areas and single amino acids with significant importance for ligand binding to this receptor.

  • 19.
    Saar, Indrek
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Runesson, Johan
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Järv, Jaak
    Kurrikoff, Kaido
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia .
    Novel Galanin Receptor Subtype Specific Ligand in Depression Like Behavior2013In: Neurochemical Research, ISSN 0364-3190, E-ISSN 1573-6903, Vol. 38, no 2, p. 398-404Article in journal (Refereed)
    Abstract [en]

    Neuropeptide galanin and its three receptors, galanin receptor type 1-galanin receptor type 3, are known to be involved in the regulation of numerous psychological processes, including depression. Studies have suggested that stimulation of galanin receptor type 2 (GalR2) leads to attenuation of the depression-like behavior in animals. However, due to the lack of highly selective galanin subtype specific ligands the involvement of different receptors in depression-like behavior is yet not fully known. In the present study we introduce a novel GalR2 selective agonist and demonstrate its ability to produce actions consistent with theorized GalR2 functions and analogous to that of the anti-depressant, imipramine.

  • 20.
    Saar, Indrek
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Runesson, Johan
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    McNamara, Ilan
    Järv, Jaak
    Robinson, John K.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Novel galanin receptor subtype specific ligands in feeding regulation2011In: Neurochemistry International, ISSN 0197-0186, E-ISSN 1872-9754, Vol. 58, no 6, p. 714-720Article in journal (Refereed)
    Abstract [en]

    Galanin a 29/30-residue neuropeptide has been implicated in several functions in the central nervous system, including the regulation of food consumption. Galanin and its analogues administered intraventricularly or into the hypothalamic region of brain have been shown to reliably and robustly stimulate the consumption of food in sated rodents. Three galanin receptor subtypes have been isolated, all present in the hypothalamus, but little is known about their specific role in mediating this acute feeding response. Presently, we introduce several novel GalR2 selective agonists and then compare the most selective of these novel GalR2 subtype selective agonists to known GalR1 selective agonist M617 for their ability to stimulate acute consumption of several foods shown to be stimulated by central administration of galanin. GalR1 selective agonist M617 markedly stimulated acute consumption of high-fat milk, but neither GalR2 selective agonist affected either high-fat milk or cookie mash intake. The present results are consistent with the involvement of GalR1 in mediating the acute feeding consumption by galanin and suggest an approach applicable to exploring galanin receptor specificity in normal and abnormal behavior and physiology.

  • 21.
    Sollenberg, Ulla E.
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Runesson, Johan
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Sillard, Rannar
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Binding of Chimeric Peptides M617 and M871 to Galanin Receptor Type 3 Reveals Characteristics of Galanin Receptor–Ligand Interaction2010In: International Journal of Peptide Research and Therapeutics, ISSN 1573-3149, Vol. 16, no 1, p. 17-22Article in journal (Refereed)
    Abstract [en]

    The neuropeptide galanin is ascribed to a variety of biological effects, but selective compounds to examine the specific roles of the three receptor subtypes are currently lacking. The recently introduced chimeric peptide ligands M617 and M871 target the galanin receptors GalR1 and GalR2, respectively. These peptides have been used to examine receptor function in vitro and in vivo, but their affinity to GalR3 has not been tested. Here, we report the binding affinity of these peptides at human GalR3 and demonstrate that M617 binds GalR3 and stimulates this receptor in an agonistic manner, whereas M871 shows very low affinity towards GalR3 (Ki 49.2 ± 9.4 nM and > 10 microM respectively). An L-alanine scan of M617 revealed the importance of the ligand C-terminus in GalR3 binding, which stands in contrast to the structural requirements for binding to GalR1 and GalR2. These data provide insights into galanin receptor ligand binding that should be considered when using these compounds in functional studies.

  • 22.
    Webling, Kristin E. B.
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Runesson, Johan
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Bartfai, Tamas
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Galanin receptors and ligands2012In: Frontiers in Endocrinology, ISSN 1664-2392, E-ISSN 1664-2392, Vol. 3, no 146, p. 1-14Article in journal (Refereed)
    Abstract [en]

    The neuropeptide galanin was first discovered 30 years ago. Today, the galanin family consists of galanin, galanin-like peptide (GALP), galanin-message associated peptide (GMAP), and alarin and this family has been shown to be involved in a wide variety of biological and pathological functions. The effect is mediated through three GPCR subtypes, GalR1-3. The limited number of specific ligands to the galanin receptor subtypes has hindered the understanding of the individual effects of each receptor subtype. This review aims to summarize the current data of the importance of the galanin receptor subtypes and receptor subtype specific agonists and antagonists and their involvement in different biological and pathological functions.

1 - 22 of 22
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