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  • 1
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract— The biochemical and pharmacological characteristics of dopamine agonist and antagonist binding to rat striatal subcellular fractions were studied and compared to the localization of dopamine–sensitive adenylate cyclase activity. The highest specific activity of adenylate cyclase sensitive to dopamine was associated almost exclusively with the crude synaptic membrane fraction (P2). Using [3H]-haloperidol, [3H]apomorphine and [3H]spiroperidol as markers for the dopamine receptor, high affinity and stereoselective specific binding was observed for the crude synaptic fraction and the microsomal fraction (P3). Analysis of the binding of [3H]haloperidol to the striatal microsomal preparation revealed a homogeneous receptor site with a Kd value of 3.0 nm. The data for [3H]haloperidol binding to the crude synaptosomal fraction showed two saturable binding sites with Kd values of 2.5 nm and 12.5 nm. A similar heterogeneous binding profile was observed in the P2 fraction using [3H]apomorphine. The Kd values for [3H]apomorphine in this fraction were determined to be 1.2 nm and 7.2 nm. The effects of various biochemical parameters including ionic strength, salt concentration and pH on the binding of [3H]haloperidol to the P2 fraction were also studied. Overall, these data show that the subcellular localization of multiple binding sites in the crude synaptosomal fraction and the identification of specific binding to purified synaptosomes correlate with the subcellular distribution of striatal dopamine-sensitive adenylate cyclase activity.
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  • 2
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract— An adenylate cyclase present in the caudate nucleus of rat brain, which is selectively stimulated by low concentrations of dopamine, and which is believed to mediate dopaminergic synaptic transmission, has been characterized with respect to several properties. The parameters studied included temperature, pH, ATP concentration, Mg/ATP ratio, and metal ion specificity. The effects of other compounds, including EGTA, NaF and several guanosine nucleotides, were also tested on the dopa-mine-sensitive adenylate cyclase. In addition, the subcellular distribution of the enzyme was studied. The highest specific activity was found in subcellular fractions enriched in nerve endings. A half-maximal increase in the activity of the enzyme in a subcellular fraction occurred in the presence of 4 × 10−6 M dopamine. Fluphenazine, a dopamine antagonist, competitively inhibited the activity of the enzyme in this fraction, with a calculated inhibition constant (Ki) of 8 × 10−9M.
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  • 3
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract— An adenylate cyclase present in the caudate nucleus of the rat brain, which is selectively stimulated by low concentrations of dopamine and which is believed to mediate dopaminergic synaptic transmission has been characterized with respect to interactions with guanyl nucleotides and magnesium ions. The addition of GTP (10−5 M) or GMPPNP (10−5 M) did not alter the linear increase in cyclic AMP as a function of time in the presence and absence of dopamine. GTP did, however, inhibit basal adenylate cyclase activity in homogenates of the caudate but the dopamine-stimulated enzyme activity was not affected, thus increasing the percent stimulation produced by dopamine. This ability of GTP to increase responsiveness to dopamine was not dependent on the level of added Mg2+ in the assay medium. Conversely, GMPPNP (10−5 M) markedly lowered the basal as well as the dopamine stimulated activity as a function of magnesium in the caudate. These results suggest an important role for GTP and Mg2+ in the regulation of caudate adenylate cyclase and its activation by dopamine. In homogenates of the cortex the most dramatic effect of GTP and GMPPNP was on the potentiation of the norepinephrine effect. The guanyl nucleotides studied in the cortex did not have the inhibitory effect on basal enzyme activity as observed in homogenates of the caudate.Interactions between Mg2+ and MgATP2- and the dopamine-sensitive adenylate cyclase from the rat caudate nucleus have also been studied. The data are consistent with a bireactant sequential mechanism where Mg2+ is a required activator and free ATP4 is not a significant inhibitor of the reaction. The data show that dopamine lowered the apparent Km for free Mg2+ about 2-fold without significantly changing the Vmax. GTP and GMPPNP did not alter the apparent Km for Mg2+ but did lower the Vmax both in the presence and absence of dopamine. GMPPNP was more potent than GTP in producing these effects in the striatal enzyme. The data presented herein implicate an important role for guanyl nucleotides and Mg2+ in the regulation of brain adenylate cyclase and its activation by various neurotransmitters. Furthermore, the results also suggest that although the role for guanyl nucleotides may be equally important in various areas of the brain, the mechanisms of action of guanyl nucleotides in these areas may differ.
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