Receptor-mediated biological responses are prolonged using hydrophobized ligands

• Published in: Biosensors & bioelectronics Vol. 20; no. 6; pp. 1157 - 1164
• Main Authors: Cuyper, Marcel De, Lievens, Sylvia, Flo, Gerda, Cokelaere, Marnix, Peleman, Christa, Martins, Fernanda, Santana, Maria Helena Andrade
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Lausanne Elsevier B.V 15.12.2004; Elsevier Science
• Subjects: Animals; Biological and medical sciences; Biosensors; Biotechnology; Cholecystokinin; Cholecystokinin - administration & dosage; Cholecystokinin - chemistry; Coated Materials, Biocompatible - chemistry; Dimyristoylphosphatidylcholine - chemistry; Drug Delivery Systems - methods; Feeding Behavior - drug effects; Feeding Behavior - physiology; Food intake modulation; Fundamental and applied biological sciences. Psychology; Hormone hydrophobization; Hydrophobic and Hydrophilic Interactions; Intermembrane lipid transfer; Ligands; Liposomes - chemistry; Male; Materials Testing; Methods. Procedures. Technologies; Peptide Fragments - administration & dosage; Peptide Fragments - chemistry; Phospholipid vesicles; Protein Binding; Rats; Rats, Wistar; Receptors, Peptide - chemistry; Receptor–ligand interaction; Satiation - drug effects; Satiation - physiology; Time Factors; Two-dimensional diffusion; Various methods and equipments; Receptor–ligand interaction; Hormone hydrophobization; Intermembrane lipid transfer; Phospholipid vesicles; Cholecystokinin; Two-dimensional diffusion; Food intake modulation; Hormone; Vesicle; Rat; Hydrophobization; Ligand; Interaction; Rodentia; Phospholipid; Lipids; Vertebrata; Mammalia; Food intake; Modulation; Transfer; Receptor-ligand interaction; Hormonal receptor
• ISSN: 0956-5663; 1873-4235
• DOI: 10.1016/j.bios.2004.03.038

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, CCK 9, 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 CCK 9, 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 CCK 9 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.