Dataset Information

Daily Rhythm in Plasma N-acetyltryptamine.

ABSTRACT: Normal physiology undergoes 24-h changes in function that include daily rhythms in circulating hormones, most notably melatonin and cortical steroids. This study focused on N-acetyltryptamine, a little-studied melatonin receptor mixed agonist-antagonist and the likely evolutionary precursor of melatonin. The central issue addressed was whether N-acetyltryptamine is physiologically present in the circulation. N-acetyltryptamine was detected by LC-MS/MS in daytime plasma of 3 different mammals in subnanomolar levels (mean ± SEM: rat, 0.29 ± 0.05 nM, n = 5; rhesus macaque, 0.54 ± 0.24 nM, n = 4; human, 0.03 ± 0.01 nM, n = 32). Analysis of 24-h blood collections from rhesus macaques revealed a nocturnal increase in plasma N-acetyltryptamine (p < 0.001), which varied from 2- to 15-fold over daytime levels among the 4 animals studied. Related RNA sequencing studies indicated that the transcript encoding the tryptamine acetylating enzyme arylalkylamine N-acetyltransferase (AANAT) is expressed at similar levels in the rhesus pineal gland and retina, thereby indicating that either tissue could contribute to circulating N-acetyltryptamine. The evidence that N-acetyltryptamine is a physiological component of mammalian blood and exhibits a daily rhythm, together with known effects as a melatonin receptor mixed agonist-antagonist, shifts the status of N-acetyltryptamine from pharmacological tool to candidate for a physiological role. This provides a new opportunity to extend our understanding of 24-h biology.

SUBMITTER: Backlund PS

PROVIDER: S-EPMC5571864 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Daily Rhythm in Plasma N-acetyltryptamine.

Backlund Peter S PS Urbanski Henryk F HF Doll Mark A MA Hein David W DW Bozinoski Marjan M Mason Christopher E CE Coon Steven L SL Klein David C DC

Journal of biological rhythms 20170503 3

Normal physiology undergoes 24-h changes in function that include daily rhythms in circulating hormones, most notably melatonin and cortical steroids. This study focused on N-acetyltryptamine, a little-studied melatonin receptor mixed agonist-antagonist and the likely evolutionary precursor of melatonin. The central issue addressed was whether N-acetyltryptamine is physiologically present in the circulation. N-acetyltryptamine was detected by LC-MS/MS in daytime plasma of 3 different mammals in ...[more]

PMID: 28466676

Similar Datasets

Project description:The mammalian biological clock, located in the hypothalamic suprachiasmatic nuclei (SCN), imposes its temporal structure on the organism via neural and endocrine outputs. To further investigate SCN control of the autonomic nervous system we focused in the present study on the daily rhythm in plasma glucose concentrations. The hypothalamic paraventricular nucleus (PVN) is an important target area of biological clock output and harbors the pre-autonomic neurons that control peripheral sympathetic and parasympathetic activity. Using local administration of GABA and glutamate receptor (ant)agonists in the PVN at different times of the light/dark-cycle we investigated whether daily changes in the activity of autonomic nervous system contribute to the control of plasma glucose and plasma insulin concentrations. Activation of neuronal activity in the PVN of non-feeding animals, either by administering a glutamatergic agonist or a GABAergic antagonist, induced hyperglycemia. The effect of the GABA-antagonist was time dependent, causing increased plasma glucose concentrations only when administered during the light period. The absence of a hyperglycemic effect of the GABA-antagonist in SCN-ablated animals provided further evidence for a daily change in GABAergic input from the SCN to the PVN. On the other hand, feeding-induced plasma glucose and insulin responses were suppressed by inhibition of PVN neuronal activity only during the dark period. These results indicate that the pre-autonomic neurons in the PVN are controlled by an interplay of inhibitory and excitatory inputs. Liver-dedicated sympathetic pre-autonomic neurons (responsible for hepatic glucose production) and pancreas-dedicated pre-autonomic parasympathetic neurons (responsible for insulin release) are controlled by inhibitory GABAergic contacts that are mainly active during the light period. Both sympathetic and parasympathetic pre-autonomic PVN neurons also receive excitatory inputs, either from the biological clock (sympathetic pre-autonomic neurons) or from non-clock areas (para-sympathetic pre-autonomic neurons), but the timing information is mainly provided by the GABAergic outputs of the biological clock.

Project description:Suprachiasmatic nuclei (SCN) neurons contain an intracellular molecular circadian clock and the Cryptochromes (CRY1/2), key transcriptional repressors of this molecular apparatus, are subject to post-translational modification through ubiquitination and targeting for proteosomal degradation by the ubiquitin E3 ligase complex. Loss-of-function point mutations in a component of this ligase complex, Fbxl3, delay CRY1/2 degradation, reduce circadian rhythm strength, and lengthen the circadian period by ∼2.5 h. The molecular clock drives circadian changes in the membrane properties of SCN neurons, but it is unclear how alterations in CRY1/2 stability affect SCN neurophysiology. Here we use male and female Afterhours mice which carry the circadian period lengthening loss-of-function Fbxl3Afh mutation and perform patch-clamp recordings from SCN brain slices across the projected day/night cycle. We find that the daily rhythm in membrane excitability in the ventral SCN (vSCN) was enhanced in amplitude and delayed in timing in Fbxl3Afh/Afh mice. At night, vSCN cells from Fbxl3Afh/Afh mice were more hyperpolarized, receiving more GABAergic input than their Fbxl3+/+ counterparts. Unexpectedly, the progression to daytime hyperexcited states was slowed by Afh mutation, whereas the decline to hypoexcited states was accelerated. In long-term bioluminescence recordings, GABAA receptor blockade desynchronized the Fbxl3+/+ but not the Fbxl3Afh/Afh vSCN neuronal network. Further, a neurochemical mimic of the light input pathway evoked larger shifts in molecular clock rhythms in Fbxl3Afh/Afh compared with Fbxl3+/+ SCN slices. These results reveal unanticipated consequences of delaying CRY degradation, indicating that the Afh mutation prolongs nighttime hyperpolarized states of vSCN cells through increased GABAergic synaptic transmission.SIGNIFICANCE STATEMENT The intracellular molecular clock drives changes in SCN neuronal excitability, but it is unclear how mutations affecting post-translational modification of molecular clock proteins influence the temporal expression of SCN neuronal state or intercellular communication within the SCN network. Here we show for the first time, that a mutation that prolongs the stability of key components of the intracellular clock, the cryptochrome proteins, unexpectedly increases in the expression of hypoexcited neuronal state in the ventral SCN at night and enhances hyperpolarization of ventral SCN neurons at this time. This is accompanied by increased GABAergic signaling and by enhanced responsiveness to a neurochemical mimic of the light input pathway to the SCN. Therefore, post-translational modification shapes SCN neuronal state and network properties.

Project description:Experimental studies show that human pain sensitivity varies across the 24-hour day, with the lowest sensitivity usually occurring during the afternoon. Patients suffering from neuropathic pain, or nerve damage, experience an inversion in the daily modulation of pain sensitivity, with the highest sensitivity usually occurring during the early afternoon. Processing of painful stimulation occurs in the dorsal horn (DH), an area of the spinal cord that receives input from peripheral tissues via several types of primary afferent nerve fibers. The DH circuit is composed of different populations of neurons, including excitatory and inhibitory interneurons, and projection neurons, which constitute the majority of the output from the DH to the brain. In this work, we develop a mathematical model of the dorsal horn neural circuit to investigate mechanisms for the daily modulation of pain sensitivity. The model describes average firing rates of excitatory and inhibitory interneuron populations and projection neurons, whose activity is directly correlated with experienced pain. Response in afferent fibers to peripheral stimulation is simulated by a Poisson process generating nerve fiber spike trains at variable firing rates. Model parameters for fiber response to stimulation and the excitability properties of neuronal populations are constrained by experimental results found in the literature, leading to qualitative agreement between modeled responses to pain and experimental observations. We validate our model by reproducing the wind-up of pain response to repeated stimulation. We apply the model to investigate daily modulatory effects on pain inhibition, in which response to painful stimuli is reduced by subsequent non-painful stimuli. Finally, we use the model to propose a mechanism for the observed inversion of the daily rhythmicity of pain sensation under neuropathic pain conditions. Underlying mechanisms for the shift in rhythmicity have not been identified experimentally, but our model results predict that experimentally-observed dysregulation of inhibition within the DH neural circuit may be responsible. The model provides an accessible, biophysical framework that will be valuable for experimental and clinical investigations of diverse physiological processes modulating pain processing in humans.

Dataset Information

Daily Rhythm in Plasma N-acetyltryptamine.

Publications

Daily Rhythm in Plasma N-acetyltryptamine.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets