Summary
Pergolide is an ergotamine derivative with potent D1 and D2 receptor activity. In this study we showed that pergolide binds tightly to dopamine D2 short receptors, as indicated by the long period of occupancy of the receptors after washing. Furthermore, pergolide induces receptor internalization to a larger extent than dopamine, seeing that no recycling of the receptors to the plasma membrane was observed for either agonist. The dissociation of pergolide from dopamine receptors occurs during the endocytotic process, leaving the receptors accessible to [3H]methylspiperone. Pergolide is a lipophilic compound that can reach and compete with [3H]methylspiperone for binding to sequestered receptors. If internalized receptors are still a target for drug action, pergolide could be a suitable compound of therapeutic interest in cases where receptor sequestration could prevent dopamine efficacy, as in levodopa therapy.
Similar content being viewed by others
References
Cullen BR (1987) Use of eucaryotic expression technology in the functional analysis of cloned genes. Methods Enzymol 152: 684–704
Fisher SK (1988) Recognition of muscarinic cholinergic receptors in human SK-N-SH neuroblastoma cells by quaternary and tertiary ligands is dependent upon temperature, cell integrity, and the presence of agonists. Mol Pharmacol 33: 414–422
Goldstein M, Lieberman A, Lew J, Asano T, Rosenfeld MR, Makman MH (1980) Interaction of pergolide with central dopaminergic receptors. Proc Natl Acad Sci USA 77: 3725–3728
Harden TK, Petch LA, Traynelis SF, Waldo GL (1985) Agonist-induced alteration in the membrane form of muscarinic cholinergic receptors. J Biol Chem 260: 13060–13066
Itokawa M, Toru M, Ito K, Tsuga H, Kameyama K, Haga T, Arinami T, Hamaguchi H (1996) Sequestration of the short and long isoforms of dopamine D2 receptors expressed in Chinese hamster ovary cells. Mol Pharmacol 49: 560–566
Lemberger L, Crabtree RE (1979) Pharmacologic effects in man of a potent, long-acting dopamine receptor agonist. Science 205: 1151–1153
Lew JY, Nakamura S, Battista AF, Goldstein M (1970) Dopamine agonist potencies of ergolines. Psychopharmacology 3: 179–183
Masters SB, Quinn MT, Brown JH (1985) Agonist-induced desensitization of muscarinic receptor-mediated calcium efflux without concomitant desensitization of phosphoinositide hydrolysis. Mol Pharmacol 27: 325–332
Monsma FJ, McVittie LD, Gerfen CR, Mahan LC, Sibley DR (1989) Multiple D2 dopamine receptors produced by alternative RNA splicing. Nature 342: 926–929
Ng GYK, Mouillac B, George SR, Caron M, Dennis M, Bouvier M, O'Dowd BF (1994) Desensitization, phosphorylation and palmitoylation of the human dopamine D1 receptor. Eur J Pharmacol (Mol Pharmacol Sect) 267: 7–19
O'Dowd BF (1993) Structures of dopamine receptors. J Neurochem 60: 804–816
Olanow CW, Fahn S, Muenter M, Klawans H, Hurtig H, Stern M, Shoulson I, Kurlan R, Grimes JD, Jankovic J, et al (1994) A multicenter double-blind placebo-controlled trial of pergolide as an adjunct to Sinemet in Parkinson's disease. Mov Disord 9: 40–47
Seeman P, Van Tol HHM (1994) Dopamine receptor pharmacology. Trends Pharmacol Sci 15: 264–270
Von Zastrow M, Kobilka BK (1994) Antagonist-dependent and -independent steps in the mechanism of adrenergic receptor internalization. J Biol Chem 269: 18448–18452
Yu SS, Lefkowitz RJ, Hausdorff WP (1993) β-adrenergic receptor sequestration: a potential mechanism of receptor resensitization. J Biol Chem 268: 337–341
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Barbier, P., Colelli, A., Maggio, R. et al. Pergolide binds tightly to dopamine D2 short receptors and induces receptor sequestration. J. Neural Transmission 104, 867–874 (1997). https://doi.org/10.1007/BF01285554
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01285554