Substitution of conserved glycine residue by alanine in natural and synthetic neuropeptide ligands causes partial agonism at the stomoxytachykinin receptor.
A few naturally occurring insect tachykinin-related peptides, such as stomoxytachykinin (Stc-TK), contain an Ala-residue instead of the highly conserved Gly-residue that is present in most other members of this peptide family. Stc-TK is a potent, partial agonist of the stable fly (Stomoxys calcitrans) tachykinin receptor, STKR. By means of synthetic analogues, the Gly/Ala exchange, representing the addition of a single methyl group in the active core region of these peptides, was shown to be fully responsible for the generation of this partial agonism, which was also accompanied by an increase in agonistic potency. Surprisingly, this Ala-dependent reduction in maximal response levels was only observed for the agonist-induced cellular calcium rise. Stomoxytachykinin, Stc-TK, did not display partial agonism for the STKR-mediated cyclic AMP response. A possible explanation for this differential partial agonism is that the Gly-containing and Ala-replaced peptides recognize and stabilize active receptor conformations that differ in their functional coupling efficacies towards these response pathways. Drosotachykinins, Drm-TK, tachykinin-like peptides encoded in the fruit fly genome, were shown to be STKR-agonists. Interestingly, one of these peptides, which contains an Ala-residue instead of the conserved Gly-residue, also proved to be a potent, partial agonist for STKR.
Poels
Jeroen
J
Laboratory for Developmental Physiology, Genomics and Proteomics, Zoological Institute KU Leuven, Leuven, Belgium.
Van Loy
Tom
T
Franssens
Vanessa
V
Detheux
Michel
M
Nachman
Ronald J
RJ
Oonk
Hendrica B
HB
Akerman
Karl E
KE
Vassart
Gilbert
G
Parmentier
Marc
M
De Loof
Arnold
A
Torfs
Herbert
H
Broeck
Jozef Vanden
JV
D000331:Aequorin / Q000235:genetics / Q000378:metabolism; D000409:Alanine; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D000818:Animals; D001059:Apoproteins / Q000235:genetics / Q000378:metabolism; D001681:Biological Assay; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D017124:Conserved Sequence; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster; D005998:Glycine; D006110:Grasshoppers; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008163:Luminescent Measurements; D008969:Molecular Sequence Data; D009117:Muscidae; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D018039:Receptors, Tachykinin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D015320:Tachykinins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D019076:Transgenes
D001059:Apoproteins; D019476:Insect Proteins; D008024:Ligands; D009479:Neuropeptides; D018039:Receptors, Tachykinin; D011994:Recombinant Proteins; D015320:Tachykinins; C060014:apoaequorin; D000331:Aequorin; D000242:Cyclic AMP; D000409:Alanine; D002118:Calcium; D005998:Glycine