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Cyclic Monophosphate and the Activity of Tyrosine Hydroxylase in the Rat Superior Cervical Ganglion by Three Neuropeptides of the Secretin Family’

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Cyclic Monophosphate and the Activity of Tyrosine Hydroxylase in the Rat Superior Cervical Ganglion by Three Neuropeptides of the Secretin Family’ 0270.6474/85/0507-1947$02,00/O The Journal of Neuroscience CopyrIght0 Societyfor Neuroscience Vol. 5, No. 7, pp. 1947-1954 Printed I” U.S.A. July 1985 Regulation of the Concentration of Adenosine 3’,5’-Cyclic Monophosphate and the Activity of Tyrosine Hydroxylase in the Rat Superior Cervical Ganglion by Three Neuropeptides of the Secretin Family’ N. Y. IP,2 C. BALDWIN, AND R. E. ZIGMOND3 Department of Pharmacology, Harvard Medical School, Boston, Massachusetts 027 75 Abstract the increase in TH activity produced by these peptides. The nicotinic agonist dimethylphenylpiperazinium also increased Preganglionic nerve stimulation leads to an acute elevation TH activity but did not alter CAMP levels. In contrast, the of tyrosine hydroxylase (TH) activity in the rat superior cer- ability of this nicotinic agonist to increase TH activity, but not vical ganglion. This effect is mediated in part by acetylcho- that of secretin or VIP, was highly dependent on the calcium line, acting via nicotinic receptors, and in part by a noncho- concentration of the medium. Since nicotinic stimulation is linergic neurotransmitter. As a first step in an attempt to known to increase calcium entry into ganglion cells, we identify this noncholinergic transmitter, we have examined a hypothesize that calcium is the second messenger mediating number of biogenic amines, purine nucleotides, neuropep- the increase in TH activity produced by nicotinic agonists. tides, and other compounds for their ability to increase TH These results indicate that secretin, VIP, PHI, or a related activity. Secretin, vasoactive intestinal peptide (VIP), and PHI peptide may play an important role in regulating catechol- (a 27-amino acid peptide with an NHp-terminal histidine and amine synthesis in sympathetic neurons and perhaps in a COOH-terminal isoleucine amide), all members of the se- regulating other CAMP-dependent processes. The data also cretin family of peptides, increased TH activity acutely. Hu- suggest that TH activity in sympathetic ganglia is acutely man pancreatic growth hormone-releasing factor, glucagon, regulated by more than one intracellular mechanism. and gastric inhibitory peptide (three other members of this peptide family) and all other transmitter candidates tested had no effect on this enzyme activity. In the past decade, the number of “putative” neurotransmitters We have examined the possibility that this peptidergic under investigation has increased more than 3-fold. This increase is regulation of TH activity is mediated via changes in adeno- due almost entirely to the discovery of a large number of biologically sine 3’,5’-cyclic monophosphate (CAMP) levels. When the active peptides in the central and peripheral nervous systems (Krie- six members of the secretin family were tested for their ger et al., 1983). In many cases, the only evidence that these ability to increase CAMP levels in the ganglion, secretin, VIP, peptides may play an important role in the nervous system is that and PHI significantly increased this cyclic nucleotide, they are concentrated in specific parts of the central and/or periph- whereas growth hormone-releasing factor, glucagon, and eral nervous system. Little is known about the function of specific gastric inhibitory peptide produced no significant effects. peptides in these systems. The rank orders of potency and of efficacy of secretin, VIP, Among the most extensive investigations of peptides as neuro- and PHI in altering TH activity and CAMP levels were identical. transmitters are studies in sympathetic ganglia. Due to the relative Furthermore, a strong correlation was found between the simplicity of the anatomy and pharmacology of these neural struc- CAMP level and the TH activity in individual ganglia exposed tures, they are highly suitable for such investigations. A peptide to these peptides. Finally, 8-bromoadenosine 3’,5’-cyclic which resembles, although it probably is not identical to, luteinizing monophosphate and forskolin also increased TH activity. We hormone-releasing hormone has been shown to be released by hypothesize that CAMP is the second messenger mediating preganglionic neurons in the 9th and 10th paravertebral ganglia of the frog (Jan and Jan, 1982). Histochemical studies indicate that this peptide is likely to be released by the same preganglionic Received July 26, 1984; Revised December 10, 1984; neurons which release acetylcholine. Substance P has been shown Accepted December 11, 1984 to be released in the inferior mesenteric ganglion of the guinea pig ’ We would like to thank Dr. James Nathanson and Mr. Ed Hunnlcut for by neurons having cell bodies located in dorsal root ganglia (Dun their help in setting up the CAMP assay and for their generous gift of CAMP and Jiang, 1982; Tsunoo et al., 1982). In the cases just cited, the binding protein. We would also like to thank Drs. Alice Liu, Michael Goy, peptides produce long-lasting depolarizations in the neurons on Jonathan Smith. and Keith Miller for many helpful discussions. This work was which they act. However, the functional significance of these slow supported by United States Public Health Service Grant NS1.2651. N. Y. I. changes in membrane potential remains to be determined. It is was supported by National Institutes of Health Postdoctoral Training Grant possible, for example, that in certain cases the most important effect NS07009, and R. E. Z. was supported by National Institute of Mental Health of transmitters which produce relatively small depolarizations on a Research Scientist Development Award MH00162. slow (second to minute) time scale may be biochemical rather than * Present address: Laboratory of Cellular Gene Expression and Regulation, electrophysiological in nature. Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New \iork, We have recently found that two neuropeptides, secretin and NY 10021. vasoactive intestinal peptide (VIP), can produce an acute increase ’ To whom correspondence should be addressed. in the activity of tyrosine 3-monooxygenase (tyrosine hydroxylase 1947 Vol. 5, No. 7, July 1985 TABLE I TABLE II Effects of various biogenic amines, purine nucleotides, and other The effect of various peptides on TH activity and CAMP content in the compounds on TH activity in the superior cervical gang/ion superior cervical gang/ion Ganglia were preincubated for 30 min with control medium and then In most cases dopa synthesis was measured during a 30.min incubation incubated for 30 min with brocresine (150 FM) and with the compounds with one of the peptides (10 PM) and brocresine. In the case of human listed below at the concentrations indicated. The amount of dopa accumu- pancreatic growth hormone-releasing hormone (hpGRF; 10 PM) and avian lated during the incubation period was determined. The rate of dopa synthesis pancreatic polypeptide (5 PM) ganglia were preincubated with the peptides is expressed as a percentage of the rate found In ganglia incubated in the for 60 min, and then brocresine was added and the incubation continued for presence of medium containing brocresine alone (mean + SEM). The 15 min. For each peptide, the rate of dopa synthesis was compared to that average rate of dopa synthesis under these control conditions was 37 + 2 in ganglia incubated under comparable conditions but with no peptide pmol/ganglion/30 min. Each value represents the mean of three to four included in the medium. The mean control rate of dopa synthesis was 45 + ganglia. In the experiments wrth dopamine, norepinephrine, and isoproterenol 3 pmol/ganglion/30 min. Each value represents the mean f SEM of three to (except the second experiment with 10 pM isoproterenol), desmethylimipra- five ganglia except glucagon (n = 8) VIP (n = 12) and secretin (n = 12). mine (10e5 M) was added to block catecholamine uptake. CAMP content was measured after a 10.min incubation with each of the Dopa Syntheses peptides (10 PM) except in experiments with gastric inhibitory peptide, Compound (% control) cholecystokinin octapeptide, and motilin, in which a 30.min incubation was used. The data represent the means + SEM of four ganglia except for VIP Dopamine (n = 36) and secretin (n = 26). The mean control CAMP content was 1.2 + (1 FM) 88 f 7 0.1 pmol/ganglion. (10 GM) 90 + 4 Noreprnephrine Peptrde Dopa Synthesis CAMP Content (% control) f% control) (1 PM) 79 f 4 (10 PM) 101 +6 Secretin family lsoproterenol VIP 450 f 29” 724 + 44’ (1 KM) 106 f 15 Secretin 328 + 17a 357 + 13a (10 PM) 101 f4 PHI 191 f lia 258 + 42’ (10 PM) 122f7 hpGRF 102&6 84+ 10 Serotonin Glucagon 93 + 4 99 + 23 (10 PM) 93 -t 5 Gastric inhibitory peptide 87 + 5 69 f 9 Histamine Other peptides (10 PM) 99 + 9 Neuropeptide Y 90 + 8 ND” Adenosine Avian pancreatic polypeptide 96&13 ND (500 PM) 92 + 1 [Arg’]Vasopressin 120&a ND Chloroadenosine a Significantly greater than control ganglia (p < 0.001). (100 PM) 93*10 Adenosine triphosphate ’ Significantly greater than control ganglia (p < 0.025). ’ ND, not determined. (100 PM) 78 + 8 Prostaglandin E, Materials and Methods (30 nM) loak6 Male Sprague-Dawley rats (100 to 125 gm at the time of shipment from a Without desmethylimipramine (1 Oe5 M). Charles River Breeding Laboratories, Wilmington, MA) were housed for about (TH); EC 1.14.16.2) in the rat superior cervical ganglion (Ip et al., a week in indrvidual plastic cages under controlled lighting (12 hr light:12 h 1982a). This enzyme catalyzes the rate-limiting step in catechol- dark) with ad libifum access to Purina Rat Chow and water. The rats were amine biosynthesis and has been shown to be controlled by a killed by cervical dislocation, and the superior cervical ganglia were removed variety of regulatory mechanisms (Weiner et al., 1977; Zigmond, and desheathed. 1980). For example, in the rat superior cervical ganglion, increased Measurement of TH activity. TH activity was assessed by measuring the rate of dopa accumulation in the presence of a dopa decarboxylase inhibitor preganglionrc nerve activity leads to a delayed and long-lasting (Ip et al., 1982b).
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