Neurotransmitter receptor alterations in Parkinson's disease.
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Neurotransmitter-receptor binding sites for apparent muscarinic cholinergic, beta-adrenergic, gamma-aminobutyric acid and serotonin receptors were measured in the caudate nucleus and frontal cerebral cortex from post-mortem brains of 16 patients with Huntington's chorea and 16 controls. In addition, the samples were assayed for the gamma-aminobutyric-acid-synthesizing enzyme, glutamic acid decarboxylase, and for the acetylcholine-synthesizing enzyme, choline acetyltransferase. In the caudate nucleus of choreic brain, both enzyme activities were markedly lower, with significant decreases in muscarinic cholinergic and serotonin receptor binding, whereas enzyme activities and receptor binding were unchanged in the cerebral cortex. By contrast, gamma-aminobutyric acid and beta-adrenergic receptor binding were not significantly different in choreic and control caudate nucleus or cortex, suggesting that, despite the loss of gamma-aminobutyric-acid-synthesizing ability in the corpus striatum, gamma-aminobuytric acid mimetic drugs might alleviate the movement disorders in Huntington's chorea.
BACKGROUND: The nervous system is increasingly recognized to play a critical role in tumor initiation and progression. Central to this complex relationship are the interactions between neurotransmitters secreted by neurons and their receptors (neurotransmitter receptors, NTRs) expressed on cancer cells, which activate multiple intracellular signaling pathways. However, the spectrum of NTR dysregulation and its association with biochemical recurrence (BCR) in prostate cancer (PCa) has not been explored. Therefore, the aim of this study was to fill this gap. METHODS: We systematically characterized the expression profiles of 130 NTR genes by integrating bulk and single-cell transcriptomic data. Consistently dysregulated NTR (cdNTR) genes were identified and used to construct a PCa signature (PCaSig) using elastic-net regression. The robustness of PCaSig was evaluated across three independent cohorts. In addition, the associations of PCaSig with clinicopathological characteristics, genomic alterations, tumor immune-related characteristics, and biological pathways were comprehensively investigated. RESULTS: Thirteen cdNTR genes with strong cell-type specificity, particularly in luminal epithelial cells, were identified. PCaSig robustly stratified patients into distinct BCR risk groups across multiple independent cohorts and remained an independent predictor after adjustment for clinicopathological factors. High PCaSig scores were associated with aggressive clinicopathological features, elevated tumor mutation burden (TMB), suppression of neurotransmitter-related signaling, and activation of cell-cycle and immune-related pathways. Notably, PCaSig refined prognostic stratification regardless of TMB status and was associated with distinct immune-related characteristics, including immune checkpoint expression and immune cell infiltration. Incorporation of PCaSig into a clinical nomogram significantly improved prognostic accuracy and clinical net benefit. CONCLUSIONS: These findings establish NTR dysregulation as a previously underappreciated dimension of PCa and support PCaSig as a clinically relevant tool for personalized management.
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The binding of 3H-quinuclidinyl benzilate, a muscarinic cholinergic antagonist, of 3H-dihydroalprenolol, a beta adrenergic antagonist, and of 3H-flunitrazepam, a ligand which labels benzodiazepine receptors, was examined in several regions of control and Friedreich's ataxia (FA) brains. 3H-Quinuclidinyl benzilate binding appeared to increase in the inferior olivory nucleus, anterior and posterior cerebellar vermi but was unaltered in the dentate nucleus and cerebellar hemisphere of FA brain. The binding of 3H-dihydroalprenolol seemed to increase in the inferior olivary nucleus yet was not different from controls in the dentate nucleus, cerebellar hemisphere, anterior and posterior cerebellar vermi of FA brains. 3H-Flunitrazepam binding was slightly lowered in the inferior olivary and dentate nuclei but was unchanged in the other FA brain regions examined. The present study suggests possible trends in neurotransmitter receptor alterations in post-mortem brain tissue of FA patients.
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Frontal cerebral cortex brain samples from schizophrenics and controls have been assayed for binding associated with muscarinic cholinergic, serotonin (5HT), gamma-aminobutyric acid (GABA), and beta-adrenergic receptors as well as for the activity of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD). Binding levels of tritium-LSD, presumably associated with postsynaptic 5HT receptors, were reduced 40% to 50% in samples from schizophrenics in three independent studies, whereas no other consistent alteration was observed in levels of binding associated with other receptors or in the activity of GAD. This change in receptor binding levels does not seem to be attributable to postmortem changes, to influence of drugs received by the patients, or to demographic features of the patient populations.
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Isolated pinnules of the gill of Aplysia contract when dopamine (DA) is perfused through the bath. The contraction is not blocked by high-Mg2+ seawater, and reflects excitatory receptors for DA on the smooth muscle cells of the gill. The pinnule often shows irregular, spontaneous contractions which are blocked by high-Mg2+ seawater and 30 mM CoCl2. These contractions reflect spontaneous activity of a peripheral nerve plexus. No other transmitter was found to be directly excitatory on the muscle fibers, although there are inhibitory receptors for serotonin (5-HT). Tactile stimulation of the pinnule evoked a two-component contractile reflex contraction due to activation of the peripheral nerve plexus. Acetylcholine, octopamine, and 5-HT but not several other transmitters depressed these responses, presumably due to inhibitory receptors on the neurons of the peripheral plexus.
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A cell line from the intima of the rabbit aorta has been established. This cell line exhibits strict contact inhibition, and morphologically resembles intimal endothelial cells. B-type blood group antigens and the presence of fibrinolytic activity also distinguish these cells from smooth muscle cells and from fibroblasts of the aortic wall. Endothelial cells were assayed for changes in levels of adenosine 3':5'-cyclic monophosphate (cAMP) and guanosine 3':5'-cyclic monophosphate (cGMP) in response to a series of vasoactive drugs. Control levels for cAMP and cGMP are 7.01 +/- 0.82 and 1.50 +/- 0.06, respectively (mean +/- SEM). Norepinephrine, acetylcholine, 5-hydroxytryptamine, and phenylephrine increased the levels of both nucleotides significantly. Propranolol (10-5 M) and phentolamine (10-5M) inhibited, respectively, the cAMP and cGMP response to norepinephrine. Angiotensin II and histamine significantly increased cGMP levels but not cAMP levels of the endothelial cells. The cGMP increases with acetylcholine were inhibited by atropine. These results indicate that the established cell line is endothelial in nature and contains cellular receptors to a variety of vasoactive agents.
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