Galanin is a 29/30 amino acid long bioactive peptide discovered over 30 years ago when C-terminally amidated peptides were isolated from porcine intestines. The name galanin originates from a combination of the first and last amino acids - G from glycine and the rest from alanine. The first 15 amino acids are highly conserved among species which indicates that the N-terminus is important for receptor recognition and subsequent binding. Galanin exerts its effects by binding to three different G-protein coupled receptors, which all differ in regional distribution, the affinity for shortened galanin fragments, as well as the G-protein signaling cascade used. At the time of publication, galanin was found to cause muscle contraction as well as hyperglycemia. Over the years, galanin has been reported to be involved in a wide variety of biological and pathological functions, for example epilepsy, food intake and depression.
Determining the specific involvement of the three different galanin receptors in several biological and pathological processes is limited by the small amount of galanin receptor selective/specific ligands available as research tools. Furthermore, the fast degradation of peptides limits the administration routes in animal studies.
This thesis aims at developing new galanin receptor-selective ligands to help delineate the involvement of the three different galanin receptors also known as the galaninergic system.
Paper 1 demonstrates that the neuroprotective effects of galanin in a kainic acid induced excitotoxic animal model was mediated through galanin receptor 1. Furthermore, a new robust protocol for evaluating G-protein signaling using a label-free real time impedance technique was presented and compared to two different classical second-messenger assays.
Paper 2 presents a series of systemically active galanin receptor 2 selective ligands subsequently evaluated in two different depression-like animal models.
In conclusion, this thesis presents six new galanin ligands, which can be used to evaluate the galaninergic system as well as to investigate the possible use of peptides as pharmaceuticals.
Stockholm: Department of Neurochemistry , 2016. , 60 p.
2016-02-08, Heilbronnsalen, C458, Svante Arrheniusv. 16B, Stockholm, 14:00 (English)