Review
Galanin receptor subtypes

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Abstract

The neuropeptide galanin, which is widely expressed in brain and peripheral tissues, exerts a broad range of physiological effects. Pharmacological studies using peptide analogues have led to speculation about multiple galanin receptor subtypes. Since 1994, a total of three G-protein-coupled receptor (GPCR) subtypes for galanin have been cloned (GAL1, gal2 and gal3). Potent, selective antagonists are yet to be found for any of the cloned receptors. Major challenges in this field include linking the receptor clones with each of the known physiological actions of galanin and evaluating the evidence for additional galanin receptor subtypes.

Section snippets

Native galanin receptors

The first binding profiles derived from native systems with galanin and related peptide analogues (Fig. 1) were consistent with multiple receptor subtypes4, 6, 7, 8, although definitive proof required cloning. Peptides displaced [125I]galanin binding to human Bowes melanoma cell membranes with a distinctive order of potency: galanin-1–30 > galanin-1–16 > d-Trp2-galanin ⪢ galanin-3–30 (Ref. 9). [125I]galanin binding sites with a difference in affinity of up to a factor of ten for galanin and

The GAL1 receptor

The first known galanin receptor GAL1 has been isolated from the human Bowes melanoma cell line34 and other sources35, 36. Human GAL1 contains 349 amino acids with the structure of a G-protein-coupled receptor (GPCR)37. The highest amino acid similarities are found with human gal2 (42%) and human gal3 (38%) receptors, the rat orphan receptor GPR54 (37%)38, and human somatostatin and opioid receptors (30–34%)39. A rat GAL1 homologue, cloned from brain40 and RIN-14b cells39, 41, contains 346

In vivo responses to galanin: comparison with cloned receptors

The effects of galanin in vivo have been studied extensively3, 5; experimental paradigms include modulation of acetylcholine release, memory and Alzheimer’s disease71, 72, feeding behaviour73, pain3, depression3, gut secretion and motility74, cardiovascular tone75, cerebrovascular tone76, neuroendocrine regulation, lacation and reproduction77 and neuroregeneration78. An in-depth discussion of these effects is beyond the scope of this review; the few models selected here are not comprehensive

Concluding remarks

It is clear that there is a lack of concordance of profiles for cloned galanin receptor subtypes with the effects of galanin-like peptides in native systems. The cloned receptors do not readily account for the reported antagonist actions of the chimeric peptides M15, M32, M35, C7 and especially M40, nor do they account for responses to galanin-3–29. Furthermore, the cloned receptors do not account for the enhanced potency or opposing actions of galanin-1-15 compared with full-length galanin.

Acknowledgements

We thank George Moralishvili for expert graphic assistance.

Glossary

Chemical names

M15:
galanin-1–13-substance-P-5–11 amide, also known as galantide
M32:
galanin-1–13-NPY25–36 amide
M35:
galanin-1–13-bradykinin-2–9 amide
M40:
galanin-1–13-Pro-Pro-Ala-Leu-Ala-Leu-Ala amide
C7:
galanin-1–13-spantide amide, substance P receptor antagonist
SCH202596:
2-[(5-methoxy-3-oxo-1-carboxymethyl)-6-spiro(1,4-cyclohexadienyl)]-(3S,4S,5S,6S)-6-[(5,7-dichloro-6-methyl-3-oxo-2,3-dihydrobenzo[b]furan-4-yl)oxyl]-3,4,5-trihydroxy-1-cyclohexene-1-methylcarboxylate

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