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Sodium Ion Modulates D2 Receptor Characteristics of Dopamine Agonist

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Sodium Ion Modulates D2 Receptor Characteristics of Dopamine Agonist Proc. NatL Acad. Sci. USA Vol. 79, pp. 4212-4216, July 1982 Neurobiology Sodium ion modulates D2 receptor characteristics of dopamine agonist and antagonist binding sites in striatum and retina (adenylate cyclase/antipsychotic drugs/neuroleptic drugs/guanine nucleotide) MAYNARD H. MAKMAN*t, B. DvoRKIN*, AND PATRICE N. KLEIN* Departments of *Biochemistry and tMolecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461 Communicated by Alex B. Novikoff, March 29, 1982 ABSTRACT Sodium ion (Na+) influences binding of both do- pharmacology and guanine-nucleotide sensitivity of both do- pamine agonists and antagonists to D2 receptors in striatum and pamine agonist (2-amino-6,7-dihydroxy-1,2,3,4-tetrahydro[5,8- retina. Also, Na+ markedly potentiates the loss of high-affinity 3H]naphthalene; [3H]ADTN) and antagonist ([3H]spiroperidol agonist binding due to the GTP analogue p[NH]ppG. 2-Amino-6, and [3H]domperidone) receptor binding to clarify relationships 7-dihydroxy-1,2,3,4-tetrahydro[5,8-3H]naphthalene ([3H]ADTN) of classes of dopamine receptors in striatum and retina. In- binds exclusively to an agonistaconformation ofD2 receptor in both cluded is an investigation of binding affinities of selective D2 striatum and retina, distinct from the antagonist conformation la- antagonists as well as the selective D2 agonist LY-141865 (15). beled by [3H]spiroperidol or [3H]domperidone in striatum or by It is concluded from- these studies that the agonist radioligand [3H]spiroperidol in retina. Nat is not required for interaction of [3H]ADTN and the antagonist ligand [3H]spiroperidol in both [3H]ADTN or antagonist radioligand sites with the selective D2 ligand [3H]- agonist LY-141865, the D2 antagonist domperidone, or nonselec- striatum and retina as well as the antagonist tive dopamine agonists or antagonists; however, Na+ is necessary domperidone in striatum label acommon D2receptor population. for high affinity interaction ofthose radioligand sites with the D2 Na+ alters the pharmacological properties of these receptors antagonists molindone and metoclopramide. With Na+ present, and is required for guanine nucleotide to enhance the rate of striatal sites for [3H]ADTN, pH]spiroperidol, and [3H]domperidone agonist dissociation from these receptors. A model is proposed have similar affinities for antagonists but only [3H]ADTN sites involving separate but interrelated effects of Na+ and guanine have high affinity for agonists. Na+ further decreases the low af- nucleotide on receptor conformation. In the presence of Na+ finity of dopamine agonists for [3H]spiroperidol binding sites. these receptors assume a conformation that corresponds to the Also, Na+ enhances [3H]spiroperidol and decreases [3H]ADTN biological activity of D2 receptor agonists and antagonists in binding. Na+ alone causes bound [3H]ADTN to dissociate from at vivo. In the presence of both Na+ and guanine nucleotide the least 30% ofstriatal and 50% ofretinal sites, and with Na+ present receptors lose sensitivity to agonists but retain sensitivity to [3H]ADTN rapidly dissociates from the remaining sites upon ad- antagonists. dition of p[NH]ppG. It is proposed that D2 receptors in striatum and retina exist in distinct but interconvertible conformational METHODS states, with different properties depending on the presence or Rat and bovine striatal and retinal membranes were prepared absence of Na+ and of guanine nucleotide. and binding assays carried out as described (13, 17-19). For routine (standard) assay with [3H]spiroperidol or [3H]dom- A number of receptor systems including the a2-noradrenergic peridone as radioligand, the incubation medium contained in and opiate systems are influenced both by GTP or related gua- addition to 0.05 M Tris HCI (pH 7.2 at 37°C) only 1 mM' MgCI2, nine nucleotide analogues and by sodium ion (Na+) (1-9). Both with or without 100 mM NaCl, in place of the mixture of ions guanine nucleotides and Na+ decrease the affinity of agonists (1 mM MgCl2/100 mM NaCl/4 mM KC/2, mM CaCl2) used for the receptor. Guanine nucleotides are involved in coupling in previous studies (13, 17, 20). Assays with [3H]ADTN were to adenylate cyclase ofreceptors that function either to activate carried out for routine (standard) assay with 1 mM. MnCl2 as or to inhibit adenylate cyclase (1). On the other hand, Na+ is described (13, 18, 21) or with 1 mM MgCl2 in place of MnCl2, involved predominantly in regulation of receptors that either with or without 100 mM NaCl, as indicated in the text. Total are not linked to adenylate cyclase or that function to inhibit specific binding represented the difference between total bind- adenylate cyclase (1, 4, 7, 9). Dopamine receptors in striatum ing.and that found in the presence of 10 ,uM (+)-butaclamol and retina appear to constitute' heterogeneous populations of (13, 18, 19). [3H]Spiroperidol (35.9 Ci/mmol; 1 Ci = 3.7 X 1010 sites (10-13). The clearest functional and biochemical evidence becquerels), [3H]domperidone (59.9 Ci/mmol), and [3H]ADTN for dopamine receptor heterogeneity is for a population of do- (34.7 Ci/mmol) were from New England Nuclear. Pergolide pamine receptors (D1) mediatingdopamine stimulation ofaden- and the structurally related partial ergoline trans-(+)-4,4a, ylate cyclase and for another population (D2) either not linked 5, 6, 7, 8, 8a, 9-octahydro-5-n-propyl-2H-pyrazolo[3,4-g]quin- to adenylate cyclase (14) or, as appears to be the case in the in- oline (LY-141865), designated as "38, R=Pro" in ref. 22, were termediate lobe ofthe pituitary, mediatingdopamine inhibition Eli ofadenylate cyclase (15). It'has been demonstrated also that the gifts from Lilly. presence of Na+ is necessary for the dopamine antagonist, sul- piride, and certain other benzamides to effectively compete for RESULTS [3H]spiroperidol binding sites in rat striatum (16). Influence of Na+ on Affinity of Dopamine Antagonists for The present study examines the influence of Na+ on the [3H]ADTN, [3H]Spiroreridol, and pH]Domperidone Binding Sites. The binding of [ H]ADTN-a pure agonist with high af- The publication costs ofthis article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertise- Abbreviation: ADTN, 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydro- ment" in accordance with 18 U. S. C. §1734 solely to indicate this fact. naphthalene. 4212 Downloaded by guest on September 23, 2021 Neurobiology: Makman et aL Proc. Natl. Acad. Sci. USA 79 (1982) 4213 Table 1. Affinities of drugs for rat striatal dopamine receptor binding sites Ki, nM [3H]ADTN [3H]Spiroperidol [3H]Domperidone Drug No NaCi With NaCi Ratio* No NaCi With NaCi Ratio* No NaCi With NaCi Ratio* Chlorpromazine 27 ± 3 30 ± 3 0.9 21 ± 6 38 ± 3 0.6 18 ± 4 5.1 ± 1.2 3.5 Domperidone 3.5 ± 1.1 4.3 ± 1.2 0.8 2.8 ± 0.1 4.2 ± 1.5 0.7 0.6 ± 0.2 0.4 ± 0.1 1.5 Molindone 790 ± 150 24 ± 3 33 1,320 ± 280 98 ± 11 14 220 ± 31 15 ± 3 15 Molindone + p[NH]ppG 760 ± 70 1,300 ± 240 Metoclopramide 2,410 ± 140 45 ± 8 57 3,320 ± 610 330 ± 50 10 618 ± 110 23 ± 4 27 Metoclopramide + p[NH]ppG 4,200 + 230 4,200 ± 400 Haloperidol 19 ± 3 15 ± 3 0.7 Fluphenazine 16 ± 4 19 ± 5 0.8 Lisuride 3.8 ± 0.5 3.0 ± 0.4 1.3 3.4 ± 0.5 12.6 ± 2.5 0.3 Pergolide 2.2 ± 0.4 3.1 ± 0.6 0.7 22.5 ± 4.3 50.0 ± 11.0 0.5 LY-141865 200 ± 60 220 ± 40 0.9 10,800 ± 800 34,400 ± 2,000 0.3 ADTN 15.3 3 18 ± 4 0.8 145 ± 40 410 ± 60 0.35 ADTN + p[NH]ppG 370 ± 60 1,180 ± 220 0.3 Binding assays were in the absence or presence of 100 mM NaCl as described in the text. p[NH]ppG was present at 100 jLM where indicated. Values are the mean ± SEM of at least three experiments. Ki values were calculated from the relationship Ki = 1C50/(1 + C/Kd), in which C represents the concentration of radioligand (3, 0.05, and 0.05 nM) and Kd, the dissociation constant (9, 0.5, and 0.15 nM) for [3H]ADTN, [3H]spiroperidol, and [3H]domperidone, respectively. Kd values are from Scatchard analyses of saturation data obtained in a separate series of experiments. * Ratio of Ki in absence of NaCl to Ki in presence of NaCl. finity and specificity for dopamine receptor sites-was studied sentially without influence on the affinity ofthese antagonists. with and without 100 mM NaCl in the assay incubation. Drugs Furthermore, LiCl was much less potent than NaCl (Fig. 2). tested included selective D2 antagonists known not to effec- A similar relative potency ofmonovalent cations has been found tively inhibit striatal or retinal dopamine-stimulated adenylate for inhibition of a2-noradrenergic (6, 25) and opiate (26-28) ag- cyclase (molindone, domperidone, and metoclopramide) as well onist binding. as antagonists capable of interacting with both D1 and D2 re- Affinity of Dopamine Agonists Including Ergolines and the ceptor systems (10, 17, 23, 24). Without Na+ present, although Partial Ergoline LY-141865 for [3H]ADTN and [3H]Spiroperidol domperidone and the nonselective antagonists (chlorproma- Binding Sites in the Presence and Absence of Na+. The er- zine, haloperidol, and fluphenazine) were effective in compet- golines lisuride (29) and pergolide (30) exert potent effects as ing for striatal [3H]ADTN binding sites, molindone and meto- dopamine agonists in vivo at sites thought to involve D2 recep- clopramide were relatively weak (Table 1; Fig. 1). Addition of tors, and both drugs have antiparkinsonism activity in man.
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