U Kahl Langel and T Bartfai 161 Introduction

Galanin was discovered in 1983 by Tatemoto et al. who isolated the 29 amino acids long neuropeptide from porcine intestine, by using a chemical method for detection of amidated C-terminals of peptides (Tatemoto etal. 1983). Since then, the galanin sequence from a large number of species has been determined (Table 16.1). In all species so far, apart from man, galanin has 29 amino acids and is C-terminally amidated. In humans the galanin sequence is 30 amino acids long, without C-terminal amidation, and instead has a free carboxyl group in its C-terminal end. The N-terminal 14 amino acids of the molecule are 100 per cent homologous in all species, with the exception of galanin from tuna fish, where the ordinary serine in position 6 is exchanged for a proline. The first 13 amino acids of galanin also constitute the part of the molecule that has been shown to be crucial for binding of galanin to galanin binding sites in the central nervous system (CNS) (Table 16.2) (Land et al. 1991). The primary sequence of the C-terminal domain of galanin varies between species, and the biological function of this part of the peptide is not completely understood. Studies of the binding of galanin(1-16) versus galanin(1-29) suggest that the C-terminal portion accounts for only 1/7 of the binding energy of the full-length peptide to its receptors in the rat brain (Land et al. 1991; Kask et al. 1996). It has been proposed that the C-terminal sequence serves as a protector to proteolytic attacks, and that it has a structure-stabilizing effect in solution. Proton NMR and CD dichroism spectroscopy studies show that the galanin structure has a different degree of rigidity depending on the environment. In water, the galanin conformation is fairly flexible and not very stable, whereas in interaction with SDS micelles, which serve as models of biological membranes, there is a much higher level of stability (Ohman et al. 1995, 1998). The proposed model is that galanin adopts a hairpinlike structure with an N-terminal fragment of galanin (galanin(1-10)) adopting an a-helical secondary structure, followed by a ß-turn around the proline in position 13 (Fig. 16.1).

The galanin cDNA encodes a precursor peptide (preprogalanin) consisting of the 29 amino acids long galanin and then a glycine, which is the amide donor for N-terminal amidation, followed by a dibasic cleavage site, and then the 60 amino acids long galanin message associated peptide (GMAP). The function of GMAP remains unknown, although it has been shown that stoichiometric quantities of GMAP are produced by galanin-producing cells.

Until recently, galanin had not been shown to belong to any known family of neuropeptides. In 1999 however, a novel galanin-related peptide was found in porcine hypothalamus. The peptide was shown to be 60 amino acids long, and to have a non-amidated

Table 16.1 Galanin sequences from different species

1

6

11

16

21

26

Human

GWTLN

SAGYL

LGPHA

VGNHR

SFSDK

NGLTS

Porcine

GWTLN

SAGYL

LGPHA

IDNHR

SFHDK

YGLA

amide

Bovine

GWTLN

SAGYL

LGPHA

LDSHR

SFQDK

HGLA

amide

Rat

GWTLN

SAGYL

LGPHA

IDNHR

SHSDK

HGLT

amide

Mouse

GWTLN

SAGYL

LGPHA

IDNHR

SFSDK

HGLT

amide

Sheep

GWTLN

SAGYL

LGPHA

IDNHR

SFHDK

HGLA

amide

Chicken

GWTLN

SAGYL

LGPHA

VDNHR

SFNDK

HGFT

amide

Bowfin

GWTLN

SAGYL

LGPHA

VDNHR

SLNDK

HGLA

amide

Alligator

GWTLN

SAGYL

LGPHA

IDNHR

SFSDK

HGIA

amide

Trout

GWTLN

SAGYL

LGPHA

IDGHR

TLSDK

HGLA

amide

Frog

GWTLN

SAGYL

LGPHA

IDNHR

SFNDK

HGLA

amide

C-terminal, and was given the name GALP, galanin-like peptide (Ohtaki et al. 1999). GALP binds to galanin receptors but GALP-specific receptors that do not bind galanin have not yet been found, despite limited expression cloning efforts using labelled GALP as ligand. The structures for rat and human GALP were also deduced from the cDNAs and show great degree of homology between the three species (porcine, human, and rat), with full conservation of the 9-21 sequence that is identical to galanin 1-13.

Both galanin and galanin receptors show a widespread anatomical distribution throughout the central and peripheral nervous systems (Fig. 16.2). In many brain regions galanin coexists with other neuropeptides and/or small molecule classical transmitters (Chan-Palay 1988; Crawley and Wenk 1989; Merchenthaler 1991; Melander et al. 1985, 1986b; Melander and Staines 1986; Skofitsch and Jacobowitz 1985; Skofitsch et al. 1989). Like many other neuropeptides, galanin often serves as a modulator of other transmitters' action. In most cases of coexistence with classical neurotransmitters the co-released galanin acts as a pre-synaptic inhibitor of the release of the classical neurotransmitters (e.g. ACh, NE, and glutamate).

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