D2-Like Receptors Mediate Dopamine-Inhibited Insulin Secretion via Ion Channels in Rat Pancreatic β-Cells
Mengmeng LiuLele RenXiangqin ZhongYaqin DingTao LiuZhihong LiuXiaohua YangLijuan CuiLijun YangYanying FanYunfeng LiuYi Zhang
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Dopamine (DA) has a vital role in the central nervous system, and also modulates lipid and glucose metabolism. The present study aimed to investigate the effect of dopamine on insulin secretion and the underlying mechanisms in rat pancreatic β-cells. Data from the radioimmunoassay indicated that dopamine inhibited insulin secretion in a glucose- and dose-dependent manner. This inhibitory effect of dopamine was mediated mainly by D2-like receptor, but not D1-like receptor. Whole-cell patch-clamp recordings showed that dopamine remarkably decreased voltage-dependent Ca2+ channel currents, which could be reversed by inhibition of the D2-like receptor. Dopamine increased voltage-dependent potassium (KV) channel currents and shortened action potential duration, which was antagonized by inhibition of D2-like receptors. Further experiments showed that D2-like receptor activation by quinpirole increased KV channel currents. In addition, using calcium imaging techniques, we found that dopamine reduced intracellular Ca2+ concentration, which was also reversed by D2-like receptor antagonist. Similarly, quinpirole was found to decrease intracellular Ca2+ levels either. Taken together, these findings demonstrate that dopamine inhibits insulin secretion mainly by acting on D2-like receptor, inhibiting Ca2+ channels and activating Kv channels. This process, in turn, results in shortened action potential duration and decreased intracellular Ca2+ levels in β-cells. This work thus offers new insights into a glucose-dependent mechanism whereby dopamine regulates insulin secretion.Keywords:
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Abstract Background Approximatively half of Alzheimer’s disease (AD) patients shows dysfunctions of the dopaminergic (DA) and serotoninergic (5HT) systems, in addition to cognitive impairment. However, the relationships between AD and the time of onset of monoaminergic disorders and their course remain poorly understood. In the present study, we characterized the DA system and the links between the 5HT and the DA systems in the TgF344‐AD rat model of AD. Method Locomotor activity tests were performed in response to the dopamine receptor 2 (D2R) agonist quinpirole. Quinpirole decreases and activates locomotion according to the dose used, which is attributable to an effect at the pre‐ and post‐synaptic D2R, respectively. The impact of the serotonin receptor 2A (5HT2AR) antagonist MDL100.907 on the quinpirole‐induced locomotion changes was also tested. In vivo SPECT molecular imaging with [ 123 I]IBZM was used for the indirect measurement of DA release in the striatum in response to MDL100.907. The densities of D2R and 5HT2AR receptors were evaluated by in situ autoradiography. Result Quinpirole stimulated locomotion in wild type (WT, +114, +170 and +65%, at 6‐, 12‐ and 18‐months) and this effect is increased in TgF344‐AD rats at all ages (+340, +300 and +103%). TgF344‐AD rats also showed an increased response to pre‐synaptic dose of quinpirole, at both 6‐ and 12‐months old. These data demonstrated a hypersensitivity of the D2R. The administration of MDL100.907 significantly exacerbated the quinpirole‐induced locomotion in WT (+40%) but not in TgF344‐AD rats, indicating a hypo‐sensitivity of the 5HT2AR. The striatal dopamine release in response to MDL100.907 was significantly higher in WT (25.6%) than in TgF344‐AD rats (10.3%), showing a reduction of the DA system control by the 5HT2AR. This effect was measured at an early stage of the disease (6 months‐old), when amyloid plaques and cognitive disorders were still slight. In addition, the density of 5HT2A receptors was decreased in DA system‐related regions (‐27% in striatum and ‐40% in subtancia nigra), without any modifications on the D2R. Conclusion TgF344‐AD rats showed functional DA system alterations and a reduction in the connectivity between the 5HT2AR and the DA system that appears early in the course of the disease.
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A 20-mer phosphorothioate oligodeoxynucleotide (D2 antisense) to the D2 antisense dopamine receptor messenger RNA (mRNA) was administered i.c.v. to mice with unilateral 6-hydroxydopamine lesions of the corpus striatum. The mice were then challenged with acute injections of various agents that cause contralateral rotational behavior, and the levels of D1 and D2 dopamine receptors and their respective mRNAs were determined in the corpus striatum. Administering the D2 antisense inhibited rotations induced by the D2 dopamine receptor agonists quinpirole and N-propyl-N-2-thienylethylamine-5-hydroxytetralin but did not block rotations induced by the D1 dopamine receptor agonist 1-phenyl-2,3,4,5-tetrahydro-1H-3 benzazepine-7,8-diol HCl or by the muscarinic cholinergic receptor agonist oxotremorine. The reduction in quinpirole-induced rotational behavior was related to the amount and length of time the D2 antisense was given. Significant reductions in behavior were seen within 1 day of repeated injections of D2 antisense, and almost complete inhibition was seen after 6 days of treatment. Recovery from inhibition occurred by 2 days after cessation of antisense treatment. Repeated treatment with D2 antisense significantly reduced the levels of D2 dopamine receptors and D2 dopamine receptor mRNA, but not the levels of D1 receptors or D1 mRNA, in the dorsolateral area of the lesioned striatum. Treatment with an oligodeoxynucleotide with randomly placed nucleotides did not inhibit quinpirole-induced rotations or alter D2 dopamine receptors or D2 dopamine receptor mRNA in either area of striatum.(ABSTRACT TRUNCATED AT 250 WORDS)
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Purpose: The purpose of this study was to explore the role and mechanism of D2 receptor (D2R) involvement in myopia development and the effects of the full D2R agonist quinpirole and partial D2R agonist aripiprazole on postnatal refractive development and form-deprivation myopia (FDM). Methods: C57BL/6 ("B6") mice, raised either in a visually normal or unilateral form-deprivation environment, were divided into three subgroups, including an intraperitoneally injected (IP) vehicle group and two quinpirole (1 and 10 µg/g body weight) treatment groups. The effects of quinpirole on FDM were further verified in D2R-knockout (KO) mice and corresponding wild-type littermates. Then, the modulation of normal vision development and FDM by aripiprazole (1 and 10 µg/g body weight, IP) was assessed in C57BL/6 mice. All biometric parameters were measured before and after treatments, and retinal cyclic adenosine phosphate (cAMP) and phosphorylated ERK (pERK) levels were analyzed to assess D2R-mediated signal transduction. Results: Neither quinpirole nor aripiprazole affected normal refractive development. FDM development was inhibited by quinpirole at low dose but enhanced at high dose, and these bidirectional effects were validated by D2R-specificity. FDM development was attenuated by the partial D2R agonist aripiprazole, at high dose but not at low dose. Quinpirole caused a dose-dependent reduction in cAMP levels, but had no effect on pERK. Aripiprazole reduced cAMP levels at both doses, but caused a dose-dependent increase of pERK in the form-deprived eyes. Conclusions: Reduction of D2R-mediated signaling contributes to myopia development, which can be selectively attenuated by partial D2R agonists that activate D2Rs under the low dopamine levels that occur with FDM.
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In vivo administration of an antisense oligonucleotide targeted toward the D2 dopamine (DA) receptor mRNA (D2 AS) markedly inhibited D2 receptor-mediated behaviors but produced only a relatively small reduction in the levels of D2 DA receptors in mouse striatum. This apparent dissociation between DA receptor-mediated behaviors and the levels of D2 DA receptors was addressed by inhibiting the total number of D2 DA receptors by intraperitoneal administration of the selective, irreversibly acting D2 DA receptor antagonist fluphenazine-N-mustard (FNM) and then determining the effects of D2 AS, administered intracerebroventricularly, on the rate of synthesis of D2 DA receptors and on the recovery of D2 receptor-mediated behaviors. FNM inactivated approximately 90% of D2 DA receptors within 4 hr of treatment, after which the receptors returned to normal levels by approximately 8 days. D2 AS treatment significantly inhibited the rate of recovery of D2 DA receptors in striatum of FNM-treated mice. FNM treatment also produced a number of behavioral alterations, including catalepsy, and the inhibition of stereotypic behavior induced by the D2/D3 DA receptor agonist quinpirole. Both of these behaviors returned to normal within 8 days after FNM treatment. D2 AS treatment delayed the restoration of these FNM-induced behaviors. Thus, it reduced the rate of disappearance of the cataleptic behavior induced by FNM and significantly delayed the restoration of the stereotypic behavior induced by quinpirole. The changes induced by D2 AS on D2 receptor-mediated behaviors were reversed on cessation of D2 AS treatment. A random oligomer given in the same amount and for the same length of time as that of the D2 AS had no significant effects on either D2 DA receptor synthesis or DA receptor-mediated behaviors. These studies demonstrate that in vivo administration of D2 AS decreased the rate of recovery of D2 DA receptors and inhibited the recovery of D2 DA receptor-mediated behaviors after irreversible receptor inactivation and suggest that D2 AS treatment inhibits the synthesis of a functional pool of D2 DA receptors.
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We examined D2-dopamine receptor containing neurons in cultures of neonatal rat striatum for apoptosis following dopamine treatment. Exposure to cultures to micromolar concentrations of dopamine resulted in 60-70% killing of D2-dopamine receptor neurons within 24 hr. We also utilized a double labeling procedure to determine that treatment with dopamine induced apoptosis in D2-dopamine receptor containing neurons. These results suggest that loss of D2-dopamine receptor containing neurons during aging could be due to an apoptotic effect of dopamine.
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