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Interaction of Ligands with the Opiate Receptors of Brain Membranes: Regulation by Ions and Nucleotides [GMP-P(NH)P/Agonists/Antagonistsi ARTHUR J

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Interaction of Ligands with the Opiate Receptors of Brain Membranes: Regulation by Ions and Nucleotides [GMP-P(NH)P/Agonists/Antagonistsi ARTHUR J Proc. Nati. Acad. Sci. USA Vol. 75, No. 4, pp. 1713-1717, April 1978 Biochemistry Interaction of ligands with the opiate receptors of brain membranes: Regulation by ions and nucleotides [GMP-P(NH)P/agonists/antagonistsI ARTHUR J. BLUME Department of Physiological Chemistry and Pharmacology, Roche Institute of Molecular Biology, Nutley, New Jersey 07110 Communicated by B. L. Horecker, January 27,1978 ABSTRACT This study shows that nucleotides, as well as this desensitization phenomenon is a result of an alteration in ions, regulate the opiate receptors of brain. GMP-P(NH)P and the agonist-receptor-adenylate cyclase complex which can be Na+ reduce the amount of steady-state specific [3H]dihydro- morphine binding and increase the rate of dissociation of the reversed by guanine nucleotides. ligand from the opiate receptor. In contrast, Mn2+ decreases the The data presented in this paper show that guanine nucleo- rate of ligand dissociation and antagonizes the ability of Na+ tides, as well as the ions, Mn2+ and Na+, do regulate brain opiate to increase dissociation. The effects of GMP-P(NH)P on receptors. A similar regulation of opiate receptors by nucleotides steady-state binding and dissociation are not reversed by has recently been observed in the neuroblastoma X glioma washing. Only GTP, GDP, ITP, and IMP-P(NH)P, in addition hybrid cell line NG108-15 (unpublished observations). The to GMP-P(NH)P, increase the rate of dihydromorphine disso- ciation. The site of nucleotide action appears to have high af- similarities and differences, between nucleotide regulation of finity: <1 &M GMP-P(NH)P produces half-maximal increases opiate receptors compared to the other plasma membrane re- in ligand dissociation. GMP-P(NH)P- and Na+-directed increases ceptors known to be coupled to adenylate cyclase are dis- in dissociation have also been found for the opiate agonists cussed. [3Hketorphine, [3HJLeu-enkephalin, and [3HJMet-enkephalin and the opiate antagonist [3H]naltrexone. Mn2+-directed de- MATERIALS AND METHODS creases in dissociation have been found for the agonist [3H- etorphine and the antagonist [3H]naltrexone. Although the [3H]Dihydromorphine (70.6 Ci/mmol), [3H]etorphine (31 plasma membrane receptors for a number of other neuro- Ci/mmol), and [3H]Leu-enkephalin (45.6 Ci/mmol) were transmitters and hormones are also regulated by guanine nu- obtained from Amersham/Searle, Des Plaines, IL; [3H]Met- cleotides, the opiate receptors appear unique because only they was New show nucleotide regulation of both agonist and antagonist enkephalin (16 Ci/mmol) from England Nuclear, binding. Boston, MA. Naloxone-HCI was obtained from Endo Labs., Garden City, NY; levallorphan was a gift from Hoffman-La Opiate agonists regulate the adenylate cyclase [ATP pyro- Roche Inc., Nutley, NJ. The nucleotides, GMP-P(NH)P, phosphate-lyase (cyclizing); EC 4.6.1.1] in neuroblastoma X AMP-P(NH)P, CMP-P(NH)P, UMP-P(NH)P, and IMP- glioma hybrid cell line NG108-15 (1-3). No clear evidence of P(NH)P, were purchased from ICN Pharmaceuticals, Irvine, opiate regulation of the adenylate cyclase of brain tissue is CA. All other nucleotides were obtained from Sigma Chemical available. However, Klee and Nirenberg (2) have in fact sug- Co., St. Louis, MO. gested that tolerance to opiates in human beings and animals Male Wistar rats (Marland Farms, Hewitt, NJ) weighing is a result of regulation of adenylate cyclase by opiates. As part 250-50 g were decapitated and their brains were rapidly re- of the search for some evidence for a "coupling" between the moved. The cerebellums were then excised, and the remainder opiate receptors of brain and its adenylate cyclase, I have in- was placed in 10 volumes of iced 50 mM Tris-HCl, pH 7.4, and vestigated the effects of nucleotides on opiate binding to rat homogenized (twice for 10 sec) in a Brinkman Polytron at 40. brain membranes. These studies were initiated since it is known The homogenates were then centrifuged at 27,000 X g for 30 that glucagon (4-6), prostaglandin E1 (7), and ,B-adrenergic (8, min at 40; the resulting pellet was washed twice with buffer and 9) receptors, which regulate adenylate cyclases, are all regulated finally suspended in 50 mM TrissHCI, pH 7.4, (2-5 mg of themselves by nucleotides. For these three classes of agonists, protein per ml). This preparation (referred to as the "Tris- agonist occupation of its receptor in the presence of guanine washed" membranes) was made 25 mM NaCl, incubated at 370 nucleotide (10-12) leads to increased adenylate cyclase activity, for 30 min, and centrifuged at 27,000 X g; the pellet was yet the presence of guanine nucleotides selectively decreases washed twice at 40 with 50 mM Tris-HCl, pH 7.4. These pellets agonist but not antagonist affinity and increases agonist disso- were then suspended in 50 mM Tris-HCI, pH 7.4, (2-5 mg ciation from the receptor. In addition, the occupation of the protein per ml) and are referred to as "Na+-washed" mem- prostaglandin E1 and f,-adrenergic receptors by only agonists branes. Membrane preparations were frozen and stored under for extended periods of time leads to a condition (termed "de- N2 until they were used. sensitization") in which agonist no longer can activate the Binding assay reactions contained 200-400 l of membranes, adenylate cyclase complex* to the same extent as they did be- 50 mM Tris-HCI (pH 7.4), [3H]ligand with or without 10 gM fore the long-term exposure to the agonist (7, 9, 13, 14). naloxone or levallorphan, and other additions (as noted in the Lefkowitz and coworkers (7, 9) have recently suggested that text) in a final volume of 0.5 ml. Reactions were terminated by addition of 2 ml of standard buffer (room temperature) and The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked * The components responsible for the catalytic activity and the binding "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate of guanine nucleotides are designated as the adenylate cyclase this fact. complex only for reasons of simplicity. 1713 Downloaded by guest on October 4, 2021 1714 Biochemistry: Blume Proc. Natl. Acad. Sci. USA 75 (1978) c 100 ._ c 4 a, 80 80 10 A BI o 0 I 60 60 a, 0 %I- ~0 0E ; 40 C :s la 0 10- 0 m .0 .0)C 0 2 I 20 0-0E 10 10 .~ X a, W0 1 2 3 4 0 20 40 60 80 O -' A,, a0. D) [3H] Dihydromorphine, [3H] Dihydromorphine nM bound FIG. 1. Tris-washed membranes were incubated with various concentrations of [3H]dihydromorphine with the following additions: 0, none; 0, 25 mM NaCl; *, 10 MM GMP-P(NH)P; *, NaCl and GMP-P(NH)P. (A) Plot of the specific [3H]dihydromorphine bound 2 4 6 8 10 0 2 4 6 8 K0 (i.e., difference ± 10MgM levallorphan). (B) Scatchard plot for the data Time, min Time, min in panel A. Ordinate, fmol of dihydromorphine bound per mg of protein/[3H]dihydromorphine in nM; abscissa, fmol of dihydromor- FIG. 2. Time course of dissociation of [3Hjdihydromorphine (A) or (B). Na+-washed membranes were incubated with phine bound per mg of protein. The lines drawn were obtained by [3H]naltrexone either 2.8 nM or 4.8 nM for 20 unweighted linear regression analysis and have a correlation coeffi- [3H]dihydromorphine [3H]naltrexone cient of 20.9. min at 32°. At this point (t = 0) 10MgM levallorphan and 25 mM NaCl, or 10 WM GMP-P(NH)P, or 1 mM MnCl2, or NaCl and GMP- P(NH)P, or NaCl and MnCl2 were added and [3H]ligand binding was followed with time. Binding plotted on the ordinate refers only to filtration over Whatman GF/B filters. Filters were washed specific binding, with that seen at t = 0 taken as 100%. Specific three times with 3 ml of standard buffer (<10 sec), dried, and binding at t = 0 of [3H]dihydromorphine and of [3H]naltrexone is 74 suspended in 10 ml of Aquasol; radioactivity was determined and 163 fmol/mg of protein, respectively. 0, No additions; ,, MnCl2; 0, NaCl; *, GMP-P(NH)P; *, NaCl and GMP-P(NH)P; v, MnCl2 at 37% counting efficiency. The binding data presented rep- and NaCl. resent only the observed specific binding of the [3H]ligand (as defined by the difference :E10 MiM nonradioactive naloxone or levallorphan). For the experiments monitoring the dissociation The presence of two different [3Hjdihydromorphine binding of [3Hlligand, binding was first allowed to proceed for 20 min sites in rat brain membranes is further supported by the ob- at 320 under the above conditions. This time was then taken as servation of the biphasic nature of the dissociation of bound t = 0. Levallorphan (10 AM) and the compounds under study dihydromorphine (Fig. 2). After a 20-min incubation in Tris (noted in text) were then added at t = 0 without significant buffer, although the major amount of the bound [8H]dihy- dilution of the reaction mixture and the amount of [3H]ligand dromorphine dissociates slowly with a t1/2 of 4.5 min, a sig- amount can seen to remaining bound was followed with time (at 320) by with- nificant (<40%) be dissociate faster with drawing aliquots and filtering them. Similar additions of test a t1/2 of <1 min. GMP-P(NH)P and Na+ (and Mn2+ as well) compounds were made at t = 0 to the tubes that had contained influence the dissociation of dihydromorphine in a complex 10MuM levallorphan during the initial 20-min period.
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