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Substance P Enhances Cholinergic Receptor Desensitization in a Clonal Nerve Cell Line (22Na+ Uptake/Receptor Modulation/Histrionicotoxin/Local Anesthetics) WILLIAM B

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Substance P Enhances Cholinergic Receptor Desensitization in a Clonal Nerve Cell Line (22Na+ Uptake/Receptor Modulation/Histrionicotoxin/Local Anesthetics) WILLIAM B Proc. Natl. Acad. Sci. USA Vol. 77, No. 1, pp. 634-638, January 1980 Neurobiology Substance P enhances cholinergic receptor desensitization in a clonal nerve cell line (22Na+ uptake/receptor modulation/histrionicotoxin/local anesthetics) WILLIAM B. STALLCUP AND JAMES PATRICK Developmental Biology and Neurobiology Laboratories, The Salk Institute for Biological Studies, P.O. Box 85800, San Diego, California 92138 Communicated by Robert W. Holley, October 3, 1979 ABSTRACT Substance P inhibits carbamylcholine-induced MATERIALS AND METHODS 22Na+ uptake in the clonal cell line PC12. This inhibition is noncompetitive with agonist but comretitive with Na+. Oc- The PC12 cell line is that derived by Greene and Tischler (11). tahydrohistrionicotoxin (H8-HTX) also e iibits this same pattern For the 22Na+ influx assays the cells were plated on polylys- of inhibition. Moreover, both substance P and HrHTX are very ine-coated 35-mm tissue culture dishes and used within 24 hr. effective in enhancing agonist-induced receptor desensitization. uptake stimulated chloride (car- Local anesthetics, such as QX222, also cause inhibition that is 22Na+ by carbamylcholine competitive with Na+, but they have only marginal effects on bachol) was measured at 220C as described (12-14). All ex- desensitization. Because substance P and HS-HTX cannot by periments were performed in the presence of 2 mM ouabain themselves cause desensitization, their action is dependent on to inhibit Na+ extrusion. Preincubation with ouabain was not and synergistic with the action of agonist. Furthermore, sub- found to be necessary. The 22Na+ uptake seen in the presence stance P and HS-HTX do not appear to compete for the same site of ouabain was subtracted from the overall rate found in the as QX222, which is thought to bind to the ion channel. Finally, substance P can stabilize the desensitized state of the receptor presence of both ouabain and carbachol. The initial rate of this even when added subsequent to the actual desensitization and carbachol-induced 22Na+ uptake was used in all of the data removal of agonist. Thus, substance P does not require open ion presented. Initial rates were determined by taking three time channels for binding and may modulate the activity o the re- points within the first 15 sec (e.g., at 5, 10, and 15 sec), so that ceptor-ionophore complex by binding to a distinct regulatory each data point is essentially the mean of three determinations. site. The standard deviation of these determinations is normally less Substance P produces excitatory depolarizing responses in a than 5%. In experiments that required medium with low Na+, number of different types of neurons (1-5). In addition, al- NaCl was replaced by sucrose to maintain osmolarity. though there is no evidence that substance P produces direct 22NaCl was obtained from Amersham. Most of the com- inhibition, there is evidence that substance P can block exci- pounds used in our study were generously given to us: synthetic tation produced by acetylcholine acting at nicotinic acetyl- substance P by Jean Rivier of The Salk Institute Peptide Biology choline receptors. For example, at the Mauthner fiber-giant Laboratory; [Leu]- and [Met]enkephalin by Nicholas Ling of fiber synapse in the hatchet fish (6), in cat Renshaw cells (7-9), The Salk Institute Neuroendocrinology Laboratory; bombesin, and in bovine adrenal chromaffin cells (10), activation of cho- somatostatin, neurotensin, 3-endorphin, luteinizing releasing linergic receptors is blocked by substance P. In the case of the factor, and a-melanocyte stimulating hormone by the Peptide Renshaw cells, the inhibition is not a consequence of interaction Biology and Neuroendocrinology Laboratories; local anesthetics of substance P with inhibitory glycine or y-aminobutyric acid by J. H. Steinbach of The Salk Institute Neurobiology Labo- receptors. Moreover, activation of glutamate receptors and ratory; pentobarbital by Jessxe Schulman of The Salk Institute muscarinic acetylcholine receptors is unaffected (7, 8). These Behavioral Neurobiology Laboratory; and synthetic octahy- results make it seem likely that the peptide exerts a selective drohistrionicotoxin (HS-HTX) by Palmer Taylor of the Phar- effect on nicotinic cholinergic receptors. Several alternative macology Department, University of California, San Diego, explanations might account for the observed inhibition: sub- CA. stance P might function as a cholinergic antagonist, as an ion channel blocker, or to modulate the activity of a receptor- RESULTS ionophore complex. Substance P inhibits carbachol-induced 22Na+ uptake in PC12 The PC12 cell line (11) has on its surface nicotinic acetyl- in a dose-dependent fashion. Fig. 1 shows the inhibition choline receptors that closely resemble those found on sympa- P the inhibition thetic neurons and Renshaw cells (12, 13). We have shown that achieved with substance and, for comparison, many of the functional properties of these receptors can be produced by two cholinergic antagonists, gallamine and d- investigated by using a 22Na+ influx assay to measure receptor tubocurarine; two local anesthetics, procaine and QX222; and activation (12-14). In this paper we use these cells to examine H8-HTX. Substance P and H8-HTX were each 50- to 100-fold the effects of substance P on activation of neuronal nicotinic more potent than the local anesthetics. Three other pep- acetylcholine receptors. Our goal has been to test the alternative tides-somatostatin, bombesin, and luteinizing releasing fac- ways in which substance P might produce its inhibitory effect tor-also inhibited carbachol-induced 22Na+ influx at 2- to and to compare substance P with other compounds that inhibit 5-fold higher concentrations than substance P, whereas receptor function through known mechanisms. a-melanocyte-stimulating hormone, neurotensin, /3-endorphin, and [Met]- and [Leu]enkephalin are without effect in this None The publication costs of this article were defrayed in part by page concentration range (data not shown). of the compounds charge payment. This article must therefore be hereby marked "ad- vertisement" in accordance with 18 U. S. C. §1734 solely to indicate Abbreviations: Carbachol, carbamylcholine chloride; H8-HTX, oc- this fact. tahydrohistrionicotoxin. 634 Neurobiology: Stallcup and Patrick Proc. Natl. Acad. Sci. USA 77 (1980) 635 blockage of flux through the ion channel, or (iii) allosteric modulation of the receptor-ionophore complex. If substance P is acting as a competitive antagonist, it should be possible to overcome its effect at high concentrations of Z100 agonist. We determined the dose dependence of carbachol C 0 activation of the receptor in the presence and absence of sub- 4.80 stance P. A double reciprocal plot of this data shows that sub- stance P behaves as a noncompetitive inhibitor of carbachol- 40 induced activation (Fig. 2A). H8-HTX also behaves in a non- 0~~~~~~~ competitive manner, but gallamine inhibits competitively, as expected of a classical cholinergic antagonist. Thus, by these criteria neither substance P nor H8-HTX interacts with the 40 agonist binding site. 20- Local anesthetics are generally thought to inhibit cholinergic function by blocking flux through the ion channel (15-17). It l-4 0 10-6 lo-, 3O0 has been postulated that the histrionicotoxins also function as [Inhibitor] ion channel blockers (18, 19), and the fact that both H8-HTX and substance P are noncompetitive with agonist suggests that FIG. 1. Inhibition of carbachol-induced 22Na+ uptake. The initial substance P could be blocking the ion channel. If these com- rate of 22Na+ uptake (receptor activity) was measured in the presence pounds block sodium influx through the ion channel, it might of 0.5 mM carbamylcholine and the indicated inhibitors. These in- hibitors were tested without preincubation-i.e., they were added at be possible to overcome that blockage by increasing the external the same time as the carbachol and 22Na+. The activity of the receptor sodium concentration. The data in Fig. 2B show that the initial is expressed as the percentage of the activity found.in the absence of rate of carbachol-stimulated 22Na+ influx saturates as the so- inhibitors. 0, d-Tubocurarine; 0, substance P; 0, H8-HTX; a, pro- dium concentration is increased. Fig. 2B also shows that the caine; o, QX222; *, gallamine. inhibition achieved by substance P or H8-HTX can be overcome by increasing the sodium concentration. This behavior is also tested had any effect on 22Na+ influx when tested alone-i.e., observed in the case of QX222, but not with gallamine, which in the absence of carbachol. appears to be noncompetitive with Na+. The competitive ef- The inhibition caused by substance P might result from (i) fects of substance P, H8-HTX, and QX222 might be due to so- competitive antagonism of agonist binding to the receptor, (ii) dium competing successfully with them either for the ion inhibition of some other aspect of receptor function, such as channel or for a second site on the receptor molecule. A B C E' 0 x 1 2 1 2 3 4 (1/[Carbacholl) X 10-3 (1/[Na+]) X 10-' FIG. 2. Kinetic analysis of effects of inhibitors. (A) 22Na+ uptake was determined as a function of carbachol concentration. The NaCl con- centration was 150 mM. When present, inhibitors were added at the same time as the carbachol and 22Na+. a, 0.2 mM gallamine; 0, 10iM substance P; 0, 10 AM H8-HTX; 3, no addition. (B) 22Na+ uptake stimulated by 0.5 mM carbachol was determined as a function of Na+ con- centration. NaCl was replaced with sucrose at NaCl concentrations below 150 mM. When present, inhibitors were added at the same time as the carbachol and 22Na+. A, 0.5 mM gallamine; v, 0.2 mM QX222; 0, 3 gM substance P; 0, 2 AM H8-HTX; 0, no addition. 636 Neurobiology: Stallcup and Patrick Proc. Natl. Acad. Sci. USA 77 (1980) a 100 A C C ae 50 \ 50 +11 0~~~~~~ C.Oi 1 2 Preincubation time, min Recovery time, min 100 C 501 [Carbachol ] 1 2 FIG.
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