Chimeric analogues of vertebrate gonadotropin-releasing hormones comprising substitutions of the variant amino acids in positions 5, 7, and 8. Characterization of requirements for receptor binding and gonadotropin release in mammalian and avian pituitary gonadotropes.

Variant forms of mammalian gonadotropin-releasing hormone (GnRH) (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly.NH2) are present in chicken ([Gln8] GnRH and [His5, Trp7, Tyr8]GnRH), salmon ([Trp7, Leu8]GnRH), and lamprey ([Tyr3, Leu5, Glu6, Trp7, Lys8] GnRH). To delineate the functional importance of the variant amino acids in positions 5, 7, and 8, the natural peptides and chimeric analogues were tested for gonadotropin-releasing activity and receptor-binding activity in rat, sheep, and chicken pituitaries. The results demonstrate that (i) the mammalian receptor has a high fidelity for Arg8 while the chicken receptor is less discriminatory and accepts basic or neutral amino acids in this position. Arg8 may contribute to conformational stabilization, and conformational constraint with D-Trp6 restored activity to analogues lacking Arg8 in the mammalian systems. D-Trp6 incorporation did not generally enhance activity in the chicken pituitary. (ii) His5 accompanying Arg8 in analogues markedly diminished activity in the chicken while gonadotropin-releasing activity was retained in the sheep pituitary. Receptor-binding activity was increased in the sheep indicating an uncoupling of receptor occupancy and activation. (iii) Substitution in position 7 is tolerated by the mammalian and chicken receptor. With Trp7-substituted analogues receptor-binding activity was relatively lower than gonadotropin-releasing activity in the sheep pituitary, suggesting an enhanced receptor activation by these analogues or the existence of different GnRH receptors.

• Publication year

  1989

• Venue

  Journal of Biological Chemistry

• Publication date

  1989-12-15

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/s0021-9258(19)30036-5PMID 2556391
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Position 7 substitutions were tolerated by mammalian and chicken receptors, and Trp7-substituted analogues showed lower receptor-binding activity than gonadotropin-releasing activity in the sheep pituitary.

  Confidence 0.90

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• His5 together with Arg8 markedly diminished chicken activity, while sheep pituitary gonadotropin release was retained and receptor-binding activity increased.

  Confidence 0.93

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• D-Trp6 restored gonadotropin-releasing activity in analogues lacking Arg8 in mammalian systems and did not generally enhance activity in the chicken pituitary.

  Confidence 0.95

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• The mammalian GnRH receptor shows high fidelity for Arg8, whereas the chicken receptor tolerates basic or neutral residues at that position.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review

• arg8

  residue

  The arginine residue at the eighth position of vertebrate GnRH used as a variable site in the analogues studied here.

  Aliases: Arg^8

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• chicken receptor

  receptor

  The GnRH receptor population in chicken pituitary gonadotropes used for binding and release assays.

  Aliases: chicken pituitary receptor

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• d-trp6

  modified residue

  A D-tryptophan substitution at position 6 that was introduced as a conformational constraint in selected analogues.

  Aliases: D-Trp^6

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• gonadotropin-releasing activity

  assay readout

  The measured ability of a peptide to stimulate gonadotropin release from pituitary gonadotropes.

  Aliases: gonadotropin release

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• his5

  residue

  The histidine residue at position 5 of selected GnRH analogues.

  Aliases: His^5

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• position 7 substitutions

  substitution pattern

  A set of amino-acid changes introduced at the seventh position of GnRH analogues.

  Aliases: substitutions in position 7

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• receptor-binding activity

  assay readout

  The measured ability of a peptide to occupy GnRH receptors in pituitary preparations.

  Aliases: receptor binding

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• sheep pituitary

  assay system

  The sheep pituitary assay system used to measure receptor binding and gonadotropin release.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• trp7-substituted analogues

  peptide analogue

  Analogue peptides carrying tryptophan at position 7 in place of the native residue.

  Aliases: Trp7 analogues

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review

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