Galanin family peptides: Molecular structure, expression and roles in the neuroendocrine axis and in the spinal cord

Abstract

Galanin is a neurohormone as well as a neurotransmitter and plays versatile physiological roles for the neuroendocrine axis, such as regulating food intake, insulin level and somatostatin release. It is expressed in the central nervous system, including hypothalamus, pituitary, and the spinal cord, and colocalises with other neuronal peptides within neurons. Structural analyses reveal that the human galanin precursor is 104 amino acid (aa) residues in length, consisting of a mature galanin peptide (aa 33-62), and galanin message-associated peptide (GMAP; aa 63-104) at the C-terminus. GMAP appears to exhibit distinctive biological effects on anti-fungal activity and the spinal flexor reflex. Galanin-like peptide (GALP) has a similar structure to galanin and acts as a hypothalamic neuropeptide to mediate metabolism and reproduction, food intake, and body weight. Alarin, a differentially spliced variant of GALP, is specifically involved in vasoactive effect in the skin and ganglionic differentiation in neuroblastic tumors. Dysregulation of galanin, GALP and alarin has been implicated in various neuroendocrine conditions such as nociception, Alzheimer's disease, seizures, eating disorders, alcoholism, diabetes, and spinal cord conditions. Further delineation of the common and distinctive effects and mechanisms of various types of galanin family proteins could facilitate the design of therapeutic approaches for neuroendocrine diseases and spinal cord injury.

Keywords: alarin; galanin; galanin-like peptide; neuroendocrine axis; spinal cord; spinal cord injury.

Figure 1

(A) Multiple sequence alignment results show that human galanin shares approximately 70% amino acid sequence identity and similarity with other galanin family proteins including rat, mouse, zebrafish, bovine, and pig. (B) A phylogenetic tree of galanin family proteins is presented using https://www.uniprot.org/align.

Figure 2

Molecular structural analyses of galanin. (A) Human galanin is comprised of a signal peptide of 19 amino acid residues (aa 1-19), a propeptide (aa 20-30), mature galanin peptide of 30 amino acid residues (aa 33-62) and the C terminal fragment, GMAP (aa 59 -123). (B) Secondary structure predicts characteristics of five alpha-helices and two beta-sheets based on bioinformatic analysis. (C, D) 3D structure analysis showing that mature galanin was predicted to resemble transportan (C), and GMAP was predicted based on the bag family molecular chaperone regulator 5 (D) using the Phyre2 web portal. (E) 3D structure analysis result of the full length of galanin is shown using the Alphafold web portal (https://alphafold.ebi.ac.uk/).

Figure 3

mRNA expression profiling of galanin gene in both human (A) and mouse (B) tissues, showing the then most highly galanin expressing tissues. These data were predicted by using bioinformatics based on the Genevisible^® (http://genevisible.com).

Figure 4

(A) Multiple sequence alignment results show that human GALP shares sequence identity or similarity to mouse, rat, pig, dog and cat. (B) A phylogenetic tree of GALP family proteins is presented using https://www.uniprot.org/align. (C) Multiple sequence alignment results show that GALP shares about 50% of sequence homology with galanin.

Figure 5

Molecular structural analyses of GALP. (A) Human GALP is comprised of a signal peptide of 24 amino acid residues (aa 1-24), Galanin-like peptide (aa 25-84) and a propeptide at the C terminus (aa 85 -116). (B) Secondary structure predicts characteristics of five alpha-helices and two beta-sheets based on bioinformatic analysis using the Phyre2 web portal. (C) 3D structure analysis of Galanin-like peptide was predicted to resemble transportan, same as that of galanin. (D) 3D structure analysis result of the full length of GALP is shown using the Alphafold web portal (https://alphafold.ebi.ac.uk/). (E) Alarin is a differentially spliced form of GALP gene which encodes a 25 amino acid neuropeptide (GenBank accession no. DQ155644). (F) Secondary structure of alarin based on bioinformatic analysis using the Phyre2 web portal.

Figure 6

mRNA expression profiling of GALP gene in both humans (A) and mouse (B) tissues, showing the ten most highly galanin expressing tissues. These data were predicted by using bioinformatics based on the Genevisible^® (http://genevisible.com).

Figure 7

Summary diagram showing the putative roles of galanin, GMAP, GALP, and alarin in various organs and disease conditions.