{'fraction_non_alphanumeric': 0.03688708951866847, 'fraction_numerical': 0.0103463787674314, 'mean_word_length': 5.801223241590214, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Is Dopamine‐Induced Inhibition of Adenylate Cyclase Involved in the Autoreceptor‐Mediated Negative Control of Tyrosine Hydroxylase in Striatal Dopaminergic Terminals?

Abstract The mechanism of the negative control of tyrosine hydroxylase (TH) activity induced by the stimulation of presynaptic 3,4‐dihydroxyphenylethylamine (dopamine, DA) autoreceptors was investigated using rat striatal slices and synaptosomes incubated under control ([K+] = 4.8 mM) or depolarizing ([K+] = 60 mM) conditions. The stimulation of DA autoreceptors by 7‐hydroxy‐2‐(di‐n‐propylamino) tetralin (1 μM 7‐OH‐DPAT) produced a significant decrease in TH activity extracted from striatal slices maintained under control conditions. This effect was associated with the complete conversion of TH into an enzyme form with a low affinity for its pterin cofactor (Km∼0.80 mM). Furthermore, compared to TH extracted from control tissues, that from 7‐OH‐DPAT‐exposed striatal slices was more sensitive to the stimulatdry effects of exogenous heparin and cyclic AMP‐dependent phosphorylation. Such changes were opposite to those induced by incubating striatal slices with the adenylate cyclase activator forskolin. Indeed, forskolin treatment completely converted TH into an enzyme form with a high affinity for its pterin cofactor (Km∼0.16 mM). Such conversion was associated with a shift in the optimal pH for TH activity from 5.8 (control) to 7.2 (forskolin). Under depolarizing conditions, the blockade by (—)‐sulpiride of the stimulation of DA autoreceptors by endogenous DA was associated with a marked activation of TH. Modifications of enzymatic characteristics triggered by (—)‐sulpiride were then similar to those induced by forskolin treatment. These data suggest that presynaptic DA autoreceptors modulate the activity of TH by controlling the degree of cyclic AMP‐dependent phosphorylation of the enzyme. The blockade by Pertussis toxin of the 7‐OH‐DPAT‐induced inhibition of TH activity is coherent with a possible negative coupling of presynaptic DA autoreceptors (closely related to the D2 type) with adenylate cyclase. Such negative coupling would account for the reduction of TH activity when presynaptic DA autoreceptors are stimulated.