Linear and cyclic N-terminal galanin fragments and analogs as ligands at the hypothalamic galanin receptor.
The neuropeptide galanin (1-29) binds with high affinity to hypothalamic receptors (KD approximately 0.9 nM) and regulates feeding behavior. The N-terminal fragments (1-16), (1-16)NH2 are high affinity (KD approximately 6 nM) full agonists in vivo and in vitro. L-Ala substitutions show that amino acid residues Gly1, Trp2, Asn5, Tyr9, and Gly12 are important for the high affinity binding of galanin (1-16). Shortening the fragment (1-16) to galanin (1-7) causes a gradual drop of affinity: galanin (1-15), (1-14), and (1-13) have submicromolar KD values and galanin (1-12) has KD approximately 3 microM. Cyclic analogs of galanin (1-12) of different ring size were synthesized by condensing Gly1 and Gly12 without or with spacer groups. These analogs, independent of ring size, had a lower affinity than the linear galanin (1-12). Derivatization of the N-terminus of galanin (1-29), (1-16), and (1-12) all resulted in a large drop of affinity for the receptors, suggesting again the importance of the free N-terminal Gly.
Land
T
T
Department of Biochemistry, Arrhenius Laboratories, Stockholm University, Sweden.
Langel
U
U
Löw
M
M
Berthold
M
M
Undén
A
A
Bartfai
T
T
D000409:Alanine / Q000031:analogs & derivatives; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D005247:Feeding Behavior / Q000187:drug effects*; D019004:Galanin; D007031:Hypothalamus / Q000502:physiology*; D008297:Male; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry; D051381:Rats; D044088:Receptors, Galanin; D011964:Receptors, Gastrointestinal Hormone / Q000737:chemistry*; D012689:Sequence Homology, Nucleic Acid
D000596:Amino Acids; D009479:Neuropeptides; D010455:Peptides; D010456:Peptides, Cyclic; D044088:Receptors, Galanin; D011964:Receptors, Gastrointestinal Hormone; D019004:Galanin; D000409:Alanine