Abstract

G protein-coupled receptors have a core consisting of seven transmembrane α-helices that is important in maintaining the structure of the receptor. We postulated that disruption of the transmembrane core may interfere with receptor function. In this study, the function of integral membrane proteins was disrupted in vivo using peptides mimicking their transmembrane domains. A peptide derived from transmembrane 7 of the D2 dopamine receptor injected unilaterally into caudate nucleus of rats challenged with apomorphine resulted in rotational behavior, indicating D2 receptor blockade. No rotational behavior was seen with a similar peptide based on the β2 adrenergic receptor and the D2 transmembrane peptide did not affect the D1 dopamine receptor, indicating that the D2 receptor-derived peptide had a specific effect. The intravenous administration of a transmembrane peptide derived from the α₁-adrenergic receptor resulted in lowered arterial blood pressure and injection of a β₁-adrenergic receptor peptide resulted in decreased heart rate. Injection of a V2 vasopressin receptor-derived transmembrane peptide resulted in increased urine output, suggesting antagonism of the effects of vasopressin. Finally, dopamine release in rat brain after cocaine administration was blocked by a transmembrane peptide based on the dopamine transporter. Circular dichroism spectroscopy of the peptides revealed α-helical structure similar to that of native transmembrane domains. Thus, transmembrane peptides can disrupt membrane proteins in vivo likely by competing with native transmembrane domains. The disruption of the hydrophobic core architecture of membrane proteins represents a novel mechanism of achieving functional inhibition that may be possible to exploit in developing novel therapeutics.