Receptor-mediated biological responses are prolonged using hydrophobized ligands.
Hormone-receptor interactions occur following three-dimensional diffusion of the ligand to the membrane-embedded receptor. However, prior hydrophobization of the ligand might restrict its movement to two dimensions along the membrane surface, and the biological response might therefore be modulated. This idea was tested using the C-terminal nonapeptide, CCK9, of the satiating hormone, cholecystokinin (CCK). The hormone was lipidated by linking it covalently to distearoylphosphatidylethanolamine via a poly(ethylene glycol) (PEG) spacer. The desired conjugate was isolated by thin-layer chromatography and incorporated into preformed small unilamellar dimyristoylphosphatidylcholine (DMPC) vesicles. The hormone-bearing vesicles were injected intraperitoneally into Wistar rats and food intake monitored. Compared to the biological effect elicited by the same amount of soluble non-derivatized CCK9, food intake reduction showed a delayed onset, but lasted for a significantly longer time. We believe this prolonged effect was due to the transfer of the derivatized CCK9 from the vesicles to the natural membrane containing the hormone receptor. Ultimately, this event may result in sustained receptor occupation and, thus, food intake reduction. The underlying mechanism for the physiological effects observed may be of relevance in interpreting results obtained using artificial measuring devices; for example, the signal produced by biosensors may be drastically affected by the hydrophobicity of the ligand.
De Cuyper
Marcel
M
Interdisciplinary Research Centre, Katholieke Universiteit Leuven--Campus Kortrijk, University Campus, B-8500 Kortrijk, Belgium. marcel.decuyper@kulak.ac.be
Lievens
Sylvia
S
Flo
Gerda
G
Cokelaere
Marnix
M
Peleman
Christa
C
Martins
Fernanda
F
Santana
Maria Helena Andrade
MH
D000818:Animals; D002766:Cholecystokinin / Q000008:administration & dosage* / Q000737:chemistry*; D020099:Coated Materials, Biocompatible / Q000737:chemistry; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D005247:Feeding Behavior / Q000187:drug effects* / Q000502:physiology*; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008081:Liposomes / Q000737:chemistry*; D008297:Male; D008422:Materials Testing; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000737:chemistry*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D018000:Receptors, Peptide / Q000737:chemistry; D012527:Satiation / Q000187:drug effects* / Q000502:physiology*; D013997:Time Factors
D020099:Coated Materials, Biocompatible; D008024:Ligands; D008081:Liposomes; D010446:Peptide Fragments; D018000:Receptors, Peptide; C053399:cholecystokinin 9; D002766:Cholecystokinin; D004134:Dimyristoylphosphatidylcholine