Neuroscience
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Interactions between the intracellular domain of ligand-gated membrane receptors and cytoplasmic proteins play important roles in their assembly, clustering, and function. In addition, protein-protein interactions may provide an alternative mechanism by which neurotransmitters activate intracellular pathways. In this study, we report a novel interaction between the GABA rho1 subunit and cellular retinoic acid binding protein in mammalian retina that could serve as a link between the GABA signaling pathway and the control of gene expression in neurons. ⋯ In the absence of the rho1 receptor, these cells showed enhanced neurite outgrowth when exposed to retinoic acid and GABA had no effect on their response to retinoic acid. In contrast, cells stably transfected with the human rho1 subunit showed a significantly reduced sensitivity to retinoic acid when exposed to GABA. These results suggest that the GABA receptor subunit effectively altered gene expression through its interaction with the cellular retinoic acid binding protein pathway.
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The Drosophila inhibitor-kappaB ortholog Cactus acts as an inhibitor of the Rel-transcription factors Dorsal and Dif. In blastoderm cells and immune competent cells, Cactus inhibits Dorsal and Dif by preventing their nuclear localization. Cactus, Dorsal and Dif are also expressed in somatic muscles, where Cactus and Dorsal, but not Dif, are enriched at the neuromuscular junction. ⋯ Interestingly, in cactus mutants the subcellular localization of Dorsal and Dif in muscle is not affected, whereas cactus protein is not detected in the nucleus. This suggests, together with the similarities between the phenotypes induced by cactus and dorsal mutations, that in larval muscles the function of Cactus might be cooperation to the transcriptional activity of Rel proteins more than their cytoplasmic retention. The similarities with inhibitor-kappaB/nuclear factor kappaB interactions and muscle pathology in mammals point to Drosophila as a suitable experimental system to clarify the complex interactions of these proteins in muscle postembryonic development and activity.
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Comparative Study
Cannabinoid-receptor 1 null mice are susceptible to neurofilament damage and caspase 3 activation.
Administered cannabinoids have been shown to ameliorate signs of CNS inflammatory disease in a number of animal models, including allergic encephalomyelitis. More recently, neuroprotective actions have been attributed to activation of the cannabinoid 1 receptor in a number of in vitro and in vivo models. One of these, chronic relapsing experimental allergic encephalomyelitis, is considered a robust analog of multiple sclerosis. ⋯ These results indicate that lack of the cannabinoid receptor 1 is associated with increased caspase activation and greater loss and/or compromise of myelin and axonal/neuronal proteins. The increase of caspase 3 in knockout mice prior to disease induction indicates a latent physiological effect of the missing receptor. The data presented further strengthen the hypothesis of neuroprotection elicited via cannabinoid receptor 1 signaling.
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Comparative Study
Cardiovascular responses to microinjection of nociceptin and endomorphin-1 into the nucleus tractus solitarii in conscious rats.
Increasing evidence suggests an active participation of nociceptinergic transmission in the central control of cardiovascular activity and reflex. In this study, the role of the classic opioid mu receptor and the nociceptin/orphanin FQ receptor, a novel opioid receptor, in the nucleus tractus solitarii (NTS) in the regulation of cardiovascular activity was investigated and compared in chronically cannulated and freely moving conscious rats. Microinjections of nociceptin, an endogenous ligand for the nociceptin receptor, into the relatively rostral NTS produced dose-related (0.04, 0.2, and 1 nmol) increases in blood pressure and heart rate. ⋯ Injection of excitatory amino acid l-glutamate (1 nmol) into the same sites caused the typical depressor and bradycardic responses. In the caudal NTS areas, nociceptin and EM-1 seemed to induce opposite responses: hypotension and bradycardia. These results suggest that the novel nociceptin receptors and traditional opioid receptors in the NTS may be independently involved in the regulation of cardiovascular activity.
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Comparative Study
Rapid damping of food-entrained circadian rhythm of clock gene expression in clock-defective peripheral tissues under fasting conditions.
Restricted feeding-induced free-running oscillation of clock genes in the liver was studied in homozygous Clock-mutant (Clock/Clock) mice. Similar to wild-type mice, Clock/Clock mice showed robust food-anticipatory behavioral activity in accordance with a restricted feeding schedule. ⋯ However, during the fasting days after temporal feeding cues were removed, the oscillation of clock genes in the liver and heart, excluding the suprachiasmatic nuclei, appeared to result in arrhythmicity in Clock/Clock mice. Thus, although the CLOCK-based molecular mechanism is not required for the expression of food-anticipatory activity, intact CLOCK protein might be involved in sustaining several cycles of peripheral circadian oscillations after restricted feeding-induced resetting.