PubMed · 138797
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1977-03-31. Hemiballismus.. https://doi.org/10.1056/nejm197703312961318
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Metabotropic glutamate receptors (mGluRs) regulate transmitter release at mammalian central synapses. However, because of the difficulty of recording from mammalian presynaptic terminals, the mechanism underlying mGluR-mediated presynaptic inhibition is not known. Here, simultaneous recordings from a giant presynaptic terminal, the calyx of Held, and its postsynaptic target in the medial nucleus of the trapezoid body were obtained in rat brainstem slices. Agonists of mGluRs suppressed a high voltage-activated P/Q-type calcium conductance in the presynaptic terminal, thereby inhibiting transmitter release at this glutamatergic synapse. Because several forms of presynaptic modulation and plasticity are mediated by mGluRs, this identification of a target ion channel is a first step toward elucidation of their molecular mechanism.
We describe an in vivo approach, in transgenic mice, aimed to identify promoter elements responsible for the induction of gamma globin expression by butyrate. Transgenic lines carrying human A gamma gene promoter truncations at position -141, -201, -382, and -730 A gamma were treated with alpha amino butyric acid (alpha ABA), and effects on gamma globin expression were analyzed at the messenger RNA level. No induction of gamma gene expression was observed in animals carrying promoters truncated at positions -141, -201, or -382 A gamma, suggesting either that butyrate response elements (BRE) are not located in the proximal gamma gene promoter or, if they were, they require the cooperation of upstream sequences for gamma gene induction. Two animals from one line carrying the -730 A gamma truncation responded to alpha ABA treatment with significant increases in gamma gene expression, indicating that a BRE is located between position -382 and -730 region of the A gamma gene promoter. Because the maximum induction by alpha ABA is observed in transgenic mice carrying a A gamma gene promoter extending to nucleotide -1350, it is likely that another butyrate responsive element is located between -730 and -1350 of the A gamma gene promoter. These results indicate that the transgenic mouse model can be used for identification of DNA regions that contain cis elements involved in gamma globin gene inducibility.
The rat retina contains dopaminergic interplexiform cells that send processes to the outer plexiform layer where dopamine is released in a light-dependent manner. We report herein that physiologically relevant concentrations of dopamine inhibited ouabain-sensitive photoreceptor oxygen consumption in dark- and light-adapted rat retinas and inhibited Na+,K+-ATPase specific activity (EC 3.6.1.37) in a rat rod outer-inner segment preparation. Experiments with the selective D1 agonist fenoldopam or D2 agonist quinpirole and experiments with dopamine plus either the D1 antagonist SCH23390 or D2/D4 antagonist clozapine showed that the inhibition of oxygen consumption and enzyme activity were mediated by D2/D4-like receptors. The amphetamine-induced release of dopamine, monitored by the inhibition of oxygen consumption, was blocked by L-2-amino-4-phosphonobutyric acid and kynurenic acid. Pharmacological and biochemical experiments determined that the IC50 values of ouabain for the alpha1-low and alpha3-high ouabain affinity isozymes of photoreceptor Na+,K+-ATPase were approximately 10(-5) and approximately 10(-7) M, respectively, and that the D2/D4-like mediated inhibition of Na+,K+-ATPase was exclusively selective for the alpha3 isozyme. The dopamine-mediated inhibition of alpha3 first occurred at 5 nM, was maximal at 100 microM (-47%), had an IC50 value of 382 +/- 23 nM, and exhibited negative cooperativity (Hill coefficient, 0.27). Prior homogenization of the rod outer-inner segment completely prevented the long-lasting inhibition, suggesting that the effect was coupled to a second messenger. Although the physiological significance of our findings to photoreceptor function is unknown, we hypothesize that these results may have relevance for the temporal tuning properties of rods.