An adenylate cyclase that is activated specifically by low concentrations of dopamine has been demonstrated in homogenates of caudate nucleus of rat brain. A half-maximal increase in the activity of the enzyme occurred in the presence of 4 ,M dopamine. Concentrations of dopamine as low as 0.3 MAM stimulated the activity of the enzyme. The adenylate cyclase activity of the homogenates was also stimulated by low concentrations of apomorphine, a substance known to mimic the physiological and pharmacological effects of dopamine. The Recent work has implicated dopamine as a neurotransmitter in the basal ganglia of the mammalian brain (1-4). In addition, a variety of behavioral and pharmacological evidence supports the concept of a "dopamine receptor" within the basal ganglia (5-7). Moreover, evidence has accumulated that Parkinsonism can result either from depletion of the dopamine in the basal ganglia or from blockade of the "dopamine receptor" (1, 3). It would, therefore, seem of considerable importance to identify the biochemical receptor with which dopamine interacts in the basal ganglia.Recent studies on the role of adenosine 3':5'-cyclic monophosphate (cyclic AMP) in ganglia of the peripheral sympathetic nervous system have led to a partial clarification of the role and mechanism of action of dopamine within these peripheral ganglia. An adenylate cyclase was demonstrated in these ganglia that was specifically stimulated by very low concentrations of dopamine (8). The demonstration of this enzyme in these ganglia, together with other evidence presented elsewhere (9-12), led to the suggestion that cyclic AMP mediates dopaminergic transmission, and thereby modulates cholinergic transmission within these ganglia. More recently, a dopamine-sensitive adenylate cyclase has been reported by Brown and Makman (13) in mammalian retina, where dopaminergic amacrine cells occur. It seemed possible, particularly in view of the known balance and interaction of cholinergic and dopaminergic mechanisms in the extrapyramidal system, that a dopamine-sensitive adenylate cyclase might mediate dopaminergic transmission in the basal ganglia, with consequent modulation of cholinergic transmission. Therefore, we undertook a search for such an enzyme in the caudate nucleus. We report the results of these studies, which demonstrate the occurrence of this enzyme, and describe some of its pharmacological properties. The similarities between the pharmacological properties of this enzyme and those of the "dopamine receptor" suggest a close relationship between these two entities. METHODS Male Sprague-Dawley rats, weighing about 200 g, were killed by decapitation. The brain was rapidly excised in a cold room (40) and placed in cold Krebs-Ringer bicarbonate buffer that contained (in mmol/liter): NaCl, 122; KC1, 3; MgSO4, 1.2; CaCl2, 1.3; KH2PO4, 0.4; NaHCO3,25;10. This buffer had previously been equilibrated with a gas mixture of 95% 02-5% C02, and had a pH of 7.4 at 250. The brainstem and cerebellum were removed, and the brain was he...
Sequence-dependent variations in DNA revealed by x-ray crystallographic studies have suggested that certain DNA-reactive drugs may react preferentially with defined sequences in DNA. Drugs that wind around the helix and reside within one of the grooves of DNA have perhaps the greatest chance of recognizing sequence-dependent features of DNA. The antitumor antibiotic CC-1065 covalently binds through N-3 of adenine and resides within the minor groove of DNA. This drug overlaps with five base pairs for which a high sequence specificity exists.
The binding of two 5-substituted-l,3,4-thiadiazole-2-thione inhibitors to the matrix metalloproteinase stromelysin (MMP-3) have been characterized by protein crystallography. Both inhibitors coordinate to the catalytic zinc cation via an exocyclic sulfur and lay in an unusual position across the unprimed (Pl-P3) side of the proteinase active site. Nitrogen atoms in the thiadiazole moiety make specific hydrogen bond interactions with enzyme structural elements that are conserved across all enzymes in the matrix metalloproteinase class. Strong hydrophobic interactions between the inhibitors and the side chain of tyrosine-I55 appear to be responsible for the very high selectivity of these inhibitors for stromelysin. In these enzymehnhibitor complexes, the S 1 ' enzyme subsite is unoccupied. A conformational rearrangement of the catalytic domain occurs that reveals an inherent flexibility of the substrate binding region leading to speculation about a possible mechanism for modulation of stromelysin activity and selectivity.
Adenylate cyclase (EC 4.6 Many antipsychotic drugs produce an extrapyramidal syndrome indistinguishable from Parkinson's disease (1, 2). There is considerable evidence that suggests that these extrapyramidal side effects may arise from the demonstrated ability of these drugs to antagonize the "dopamine receptor" of the caudate nucleus (3, 4), which many investigators have indirectly characterized in an extensive series of physiological, biochemical, and behavioral studies. Recently, a dopaminesensitive adenylate cyclase was demonstrated in homogenates of the caudate nucleus of the rat brain (5). It was suggested (5) that an intimate association exists between this dopaminesensitive adenylate cyclase and the "dopamine receptor" of the caudate nucleus, since the biochemical and pharmacological properties of this enzyme were similar to the reported properties of the caudate "dopamine receptor." A variety of evidence suggests that dopamine may serve as a neurotransmitter in several other regions of the mammalian nervous system, in addition to the caudate nucleus. Both the nucleus accumbens and the olfactory tubercle, two anatomical structures associated with the limbic system, are among the regions recently identified (6) as receiving dopaminergic innervation. Furthermore, biochemical measurements have shown the occurrence of relatively high levels of dopamine and 1113 its metabolites in these regions (refs. 7 and 8; 0. Hornykiewicz, personal communication; A. Carlsson, personal communication).The evidence that the extrapyramidal syndrome produced by the antipsychotic drugs is attributable to the ability of these drugs to block caudate dopamine receptors, together with the evidence that dopamine occurs in several other regions of the nervous system, has focused attention (e.g., refs. 9-11) on the twin hypotheses (a) that the antipsychotic drugs may achieve their therapeutic effects by virtue of blocking dopamine receptors in the brain and (b) that a hyperactivity of dopaminergic pathways in the brain may be involved in the pathophysiology of schizophrenia. The mesolimbic dopaminergic system of the brain, which projects to the olfactory tubercle and the nucleus accumbens, has figured prominently in such speculations concerning the pathophysiology of schizophrenia and the site of action of the antipsychotic drugs (11).The results presented in this communication are consistent with a model in which the dopamine receptor of neural tissue is intimately associated with a dopamine-sensitive adenylate cyclase. The results are also compatible with the possibility that inhibition of this enzyme may provide an explanation, at the molecular level, for the therapeutic effects, as well as for the side effects, of some widely used antipsychotic agents. MATERIALS AND METHODSATP, cyclic AMP, l-norepinephrine, and EGTA were purchased from Sigma; 3-hydroxytyramine (dopamine) was from CalBiochem^; inorganic salts were all reagent grade. All phenothiazines and related compounds were obtained, in high purity, from their commercia...
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