Dopamine-sensitive adenylate cyclase

Von Hungen, K., Roberts, S., and Hill, D. F. (1975) Interactions between lysergic acid diethylamide and dopamine-sensitive adenylate cyclase systems in rat brain. Brain Res., 94 57-66. 

Ahn HS, Makman MH. (1979). Interaction of LSD and other hallucinogens with dopamine-sensitive adenylate cyclase in primate brain regional differences. Brain Res. 162(1) 77-88. 

Dopamine-sensitive adenylate cyclase activity was early demonstrated in both the retina and the cervical ganglion of the cow [47] and later in homogenates of the caudate-putamen of the rat brain [48]. Kebabian has recently reviewed the biochemical components of dopamine-sensitive adenylate cyclase and the physiological role of the D1 receptor [49]. D1 and D2 agonists stimulate and inhibit adenylate cyclase activity, respectively. 

Ka for dopamine and Ki for several dopamine antagonists on dopamine-sensitive adenylate cyclase... 

Ki for haloperidol. Spiroperidol and haloperidol are of comparable potency in several dopamine-sensitive adenylate cyclase systems. 

Commentary Dopamine-Sensitive Adenylate Cyclase as a Receptor Site... 

There is no doubt that dopamine-sensitive adenylate cyclase (D site) is not involved in the antipsychotic effect of neuroleptic drugs. 

All the pharmacological and behavioural effects elicited by dopamine agonists and antagonists in the brain can only be explained if such an interaction occurs at the level of the dopamine receptor (D2 receptor site) the site still remains in search of a function. Bovine parathyroid cells were reported to possess dopamine sites which should be involved in the control of parathormone secretion. However, the very poor pharmacological characterization and the lack of in vivo evidence do not allow to assess the dopaminergic nature of this hormone secretion. Dopamine-sensitive adenylate cyclase is thus not a receptor directly implicated in the dopaminergic neurotransmission it is an enzyme which could have an important role in the control of long term metabolic effects such as the synthesis of neuronal constituents. 

How the problem arises whether or not the dopamine-sensitive adenylate cyclase (D site) (2) also answers these criteria or other criteria which justify it being called a dopamine receptor like the D2 receptor site 15-8). The purpose of the present paper is to discuss this problem especially with regard to parathormone secretion. Special attention will be paid to the pharmacological characterization of this hormone secretion. 

Is Dopamine-Sensitive Adenylate Cyclase a Dopamine Receptor ... 

In my opinion, one may assume a priori that these criteria will not be fulfilled first, if the dopamine-sensitive adenylate cyclase was really involved in the parathormone secretion, the patients treated with neuroleptics and especially with the most potent drugs on the sites (phenothiazine and thioxanthene derivatives) would have normally revealed marked changes in their parathormone secretion, just like as is the case for the prolactin secretion in fact such changes have never been observed secondly, a recent report clearly indicates that the injection of dopamine in man does not modify parathormone secretion although a marked decrease in prolactin was observed (21). There is no receptor without physiological response the study of receptor requires a multidisciplinary approach. 

At least a major part of the neostriatal dopamine-sensitive adenylate cyclase activity is not associated with the terminals of the dopamine-containing nigro-striatal neurons. Intranigral injections of 6-OH-dopamine which destroy these dopamine-... 

The pharmacological properties of the dopamine-sensitive adenylate cyclase activity in either the bovine parathyroid gland or the neostriatum are summarized by Brown and Dawson-Hughes earlier in this volume and by other authors elsewhere (89, 90). 

Activation of neostriatal tyrosine hydroxylase was observed when cyclic AMP was added to high speed supernatants from rat neostriatum (133). Intraventricular injection of dibutyryl cyclic AMP stimulated tyrosine hydroxylation in the neostriatum (134). However, it is still questionable if under physiological conditions this cyclic AMP involvement in the feedback control of tyrosine hydroxylase activity is mediated by presynaptic dopamine receptors or by presynaptic allo-receptors. In addition, if a dopamine sensitive adenylate cyclase is involved in the regulation of neostriatal tyrosine hydroxylase activity it is relevant to know if this adenylate cyclase is linked to a D-1 and/or a D-2 receptor. At this point in time experimental data are not in favour of the presence of a D-l receptor linked to an adeiylate cyclase on the varicosities of dopaminergic neurons in the neostriatum. E.g. concentrations of dopamine agonists stimulating cyclic AMP formation inhibit tyrosine... 

An important criteria of D-l dopamine agonist activity is stimulation of dopamine-sensitive adenylate cyclase (8). Table I compares the activity of the four benzazepines and dopamine as stimulants of rat striatal adenylate cyclase. All of the benzazepines are only partial agonists with SK F 82526 and SK F 85174 being about 20 times more potent than dopamine and SK F 38393 and SK F 87516 being similar in potency to dopamine. 

Clement-Cormier YC, Kebabian JW, Petzold GL, Greengard P (1974) Dopamine-sensitive adenylate cyclase in mammalian brain a possible site of action of antipsychotic drugs. Proc Natl Acad Sci USA 77 1113-1117. 

Clement-Cormier YC, Parrish RG, Petzold GL, Kerabian JW, Greengard P (1975) Characterization of a dopamine-sensitive adenylate cyclase in the rat caudate nucleus. J Neurochem 25 143-149. 

Kebabian JW, Greengard P (1971) Dopamine-sensitive adenyl cyclase possible role in synaptic transmission. Science 174 1346-1349. 

Seiler, M.P. and Markstein, R. (1982) Further characterization of structural requirements for agonists at the striatal dopamine D receptor. Studies with a series of monohydroxyaminotetralins on dopamine-sensitive adenylate cyclase and a comparison with dopamine receptor binding. Mol. Pharmacol. 22,281-289. 

Maus, M.P., Bertrand, S., Drouva, R., Rasolonjanahary, C., Kordon, J., Glowinski, J., Fremont, J. and Enjalbert, A. (1989) Differential modulation of D and D2 dopamine-sensitive adenylate cyclases by 17/ -estradiol in cultured striatal neurons and anterior pituitary cells. J. Neurochem. 52 410-418. 

Thomas, T. N., and Zemp, J. W., 1977, Inhibition of dopamine-sensitive adenylate cyclase from rat brain striatal homogenates by ascorbic acid,y. Neurochem. 28 663—665. 

Brown, J. H., and Makman, M. H., 1973, Influence of neuroleptic drugs and apomorphine on dopamine-sensitive adenylate cyclase of retina,/. Neurochem. 21 477-479. 

Kebabian, J. W., and Saavedra, J. M., 1976, Dopamine-sensitive adenylate cyclase occurs in a region of substantia nigra containing dopaminergic dendrites. Science 193 683-685. 

Kebabian, J. W., Petzold, G. L., and Greengard, P., 1972, Dopamine-sensitive adenylate cyclase in caudate nucleus of rat brain, and its similarity to the dopamine receptor, Proc. Natl. Acad. Sci. U.S.A. 69 2145-2149. 

Phillipson, O. T., and Horn, A. S., 1976, Substantia nigra of the rat contains a dopamine-sensitive adenylate cyclase. Nature (London) 261 418-420. 

Racagni, G., and Carenzi, A., 1976, The anterior amygdala dopamine-sensitive adenylate cyclase point of action of antipsychotic drugs, Pharmacol. Res. Commun. 8 149-157. 

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