Hoshikawa H et al. (2017) Genes Cells "Octopamine enhances oxidative stress resistance through the fasting-responsive transcription factor DAF-16/FOXO inC.elegans."

Honjoh S, Uno M, Hoshikawa H, Nishida E

[Genes Cells, 2017]

Dietary restriction regimens lead to enhanced stress resistance and extended life span in many species through the regulation of fasting and/or diet-responsive mechanisms. The fasting stimulus is perceived by sensory neurons and causes behavioral and metabolic adaptations. Octopamine (OA), one of the Caenorhabditis elegans neurotransmitters, is involved in behavioral adaptations, and its levels are increased under fasting conditions. However, it remains largely unknown how OA contributes to the fasting responses. In this study, we found that OA administration enhanced organismal resistance to oxidative stress. This enhanced resistance was suppressed by a mutation of the OA receptors, SER-3 and SER-6. Moreover, we found that OA administration promoted the nuclear translocation of DAF-16, the key transcription factor in fasting responses, and that the OA-induced enhancement of stress resistance required DAF-16. Altogether, our results suggest that OA signaling, which is triggered by the absence of food, shifts the organismal state to a more protective one to prepare for environmental stresses.

Zhang J et al. (2015) Biochem Biophys Res Commun "Oleanolic acid activates daf-16 to increase lifespan in Caenorhabditis elegans."

Lu L, Zhou L, Zhang J

[Biochem Biophys Res Commun, 2015]

Oleanolic acid (OA) is an active ingredient in natural plants. It has been reported to possess a variety of pharmacological activities, but very little is known about its effects of anti-aging. We investigate here whether OA has an impact on longevity invivo, and more specifically, we have examined effects of OA on the lifespan and stress tolerance in Caenorhabditis elegans (C.elegans). Our results showed that OA could extend the lifespan, increase its stress resistance and reduce the intracellular reactive oxygen species (ROS) in wild-type worms. Moreover, we have found that OA-induced longevity may not be associated with the calorie restriction (CR) mechanism. Our mechanistic studies using daf-16 loss-of-function mutant strains (GR1307) indicated that the extension of lifespan by OA requires daf-16. In addition, OA treatment could also modulate the nuclear localization, and the quantitative real-time PCR results revealed that up-regulation of daf-16 target genes such as sod-3, hsp-16.2 and ctl-1 could prolong lifespan and increase stress response in C.elegans. This study overall uncovers the longevity effect of OA and its underpinning mechanisms.

Rachel T. Wragg et al. (2007) International Worm Meeting "Tyramine and octopamine inhibit serotonin-stimulated aversive behaviors in Caenorhabditis elegans through distinct receptors and signaling pathways."

Vera M. Hapiak, Rachel T. Wragg, Gareth P. Harris, Richard W. Komuniecki, Sarah B. Miller

[International Worm Meeting, 2007]

Nematodes lack an autonomic nervous system and epinephrine/norepinephrine and instead appear to use the biogenic amines, such as serotonin (5-HT), tyramine (TA) and octopamine (OA) to modulate many rhythmic behaviors. In C. elegans, distinct TA/OA specific neurons, receptors and behaviors have been identified. In general, TA and OA oppose the action of 5-HT causing hyperactivity and inhibiting 5-HT dependent egg-laying and pumping. In the present study, we have demonstrated that both TA and OA abolish 5-HT dependent increases in responses to dilute octanol. Therefore, we have analyzed the roles of previously characterized and putative TA and OA receptors through the use of TA/OA receptor null mutants. Interestingly, TA and OA inhibit 5-HT mediated increases in octanol responsiveness through different receptors; TYRA-3 is essential for inhibition by TA and F14D12.6 is essential for inhibition by OA. In addition, responses to TA and OA desensitize after pre-exposure to the amines and this adaptation appears to be amine-specific. Inhibition binding studies using [3H]LSD confirm that membranes from mammalian cells transiently expressing either TYRA-3 or F14D12.6 exhibit highest affinity for TA or OA, respectively. f14d12.6::gfp is expressed in a number of neurons, including the ASH sensory neuron that is primarily responsible for sensitvity to dilute octanol, while tyra-3::gfp is robustly expressed in the dopaminergic ADE/CEPs. However, the individual neuron(s) required for TA or OA inhibition remain to be identified. Taken together, these results demonstrate that, although tyraminergic and octopaminergic signaling yield identical phenotypes in our behavioral assays, these amines act through separate receptors located in distinct neurons.

Komuniecki R et al. (2012) Invert Neurosci "Monoamines activate neuropeptide signaling cascades to modulate nociception in C. elegans: a useful model for the modulation of chronic pain?"

Hapiak V, Komuniecki R, Wragg R, Bamber B, Harris G

[Invert Neurosci, 2012]

Monoamines and neuropeptides interact to modulate key behaviors in most organisms. This review is focused on the interaction between octopamine (OA) and an array of neuropeptides in the inhibition of a simple, sensory-mediated aversive behavior in the C. elegans model system and describes the role of monoamines in the activation of global peptidergic signaling cascades. OA has been often considered the invertebrate counterpart of norepinephrine, and the review also highlights the similarities between OA inhibition in C. elegans and the noradrenergic modulation of pain in higher organisms.

Castillo-Quan JI et al. (2023) Sci Adv "An antisteatosis response regulated by oleic acid through lipid droplet-mediated ERAD enhancement."

Lehrbach NJ, Bland MS, Wu Z, Moronetti L, Teufl M, Blackwell TK, Castillo-Quan JI, Fernandez-Cardenas LP, Moroz N, Zhu F, Teixeira V, Pohl NK, Steinbaugh MJ

[Sci Adv, 2023]

Although excessive lipid accumulation is a hallmark of obesity-related pathologies, some lipids are beneficial. Oleic acid (OA), the most abundant monounsaturated fatty acid (FA), promotes health and longevity. Here, we show that OA benefits Caenorhabditis elegans by activating the endoplasmic reticulum (ER)-resident transcription factor SKN-1A (Nrf1/NFE2L1) in a lipid homeostasis response. SKN-1A/Nrf1 is cleared from the ER by the ER-associated degradation (ERAD) machinery and stabilized when proteasome activity is low and canonically maintains proteasome homeostasis. Unexpectedly, OA increases nuclear SKN-1A levels independently of proteasome activity, through lipid droplet-dependent enhancement of ERAD. In turn, SKN-1A reduces steatosis by reshaping the lipid metabolism transcriptome and mediates longevity from OA provided through endogenous accumulation, reduced H3K4 trimethylation, or dietary supplementation. Our findings reveal an unexpected mechanism of FA signal transduction, as well as a lipid homeostasis pathway that provides strategies for opposing steatosis and aging, and may mediate some benefits of the OA-rich Mediterranean diet.

Fanning S et al. (2018) Mol Cell "Lipidomic Analysis of -Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment."

Lou Y, Haque A, Freyzon Y, Farese RV, Terry-Kantor E, Hofbauer HF, Termine D, Welte MA, Barrasa MI, Imberdis T, Noble T, Lindquist S, Clish CB, Jaenisch R, Pincus D, Nuber S, Sandoe J, Kohlwein SD, Kim TE, Ho GPH, Ramalingam N, Walther TC, Baru V, Selkoe D, Srinivasan S, Landgraf D, Soldner F, Dettmer U, Fanning S, Becuwe M, Newby G

[Mol Cell, 2018]

In Parkinson's disease (PD), -synuclein (S) pathologically impacts the brain, a highly lipid-rich organ. We investigated how alterations in S or lipid/fattyacid homeostasis affect each other. Lipidomic profiling of human S-expressing yeast revealed increases in oleic acid (OA, 18:1), diglycerides, and triglycerides. These findings were recapitulated in rodent and human neuronal models of S dyshomeostasis (overexpression; patient-derived triplication or E46K mutation; E46K mice). Preventing lipid droplet formation or augmenting OA increased S yeast toxicity; suppressing the OA-generating enzyme stearoyl-CoA-desaturase (SCD) was protective. Genetic or pharmacological SCD inhibition ameliorated toxicity in S-overexpressing rat neurons. In a C.elegans model, SCD knockout prevented S-induced dopaminergic degeneration. Conversely, we observed detrimental effects of OA on S homeostasis: in human neural cells, excess OA caused S inclusion formation, which was reversed by SCD inhibition. Thus, monounsaturated fatty acid metabolism is pivotal for S-induced neurotoxicity, and inhibiting SCD represents a novel PD therapeutic approach.

Debnath, Arunima et al. (2021) International Worm Meeting "Neuromodulation and the relationship between Ca2+ transients and neuronal states"

Bamber, Bruce, Debnath, Arunima

[International Worm Meeting, 2021]

Neuromodulators (monoamines and neuropeptides) shape nervous system function by regulating neuronal depolarization and synaptic strengths. We are studying neuromodulation in the context of nociception, to better understand pain perception and pain treatment strategies. The ASH neuron is a major nociceptor in C. elegans. ASH senses 1-octanol and drives an aversive response, modulated by the monoamines serotonin (5-HT, potentiating) and octopamine (OA, inhibitory). To better understand neuromodulation, we are focusing on 1-octanol stimulated Ca2+ dynamics in ASH, and the quantitative relationship between Ca2+ signals and depolarization amplitudes. We showed that 5-HT potentiates ASH depolarization, but surprisingly, inhibits ASH Ca2+ transient amplitudes. These effects, like the 5-HT stimulation of behavior, depend on the SER-5 receptor in ASH. This paradoxical finding is explained by existence of a Ca2+-dependent inhibitory feedback loop: Ca2+ inhibits ASH depolarization through SLO-1 IKCa channels, and 5-HT inhibits EGL-19 L-type Ca2+ channels in ASH (via SER-5), thus disinhibiting the neuron. We are currently investigating modulation of 1-octanol responses by OA. OA inhibits 1-octanol behavioral responses, and antagonizes 5-HT potentiation, dependent on the OCTR-1 receptor in ASH. OA also inhibits ASH Ca2+ transients, representing another paradox: how can OA and 5-HT have opposite effects on ASH-dependent aversive behaviors, but the same effect on ASH Ca2+ transients? Our results show that 5-HT and OA utilize distinct signaling pathways in ASH (Galphaq for 5-HT and Galphao for OA), and that OA does not inhibit EGL-19. We are currently testing the hypothesis that OA hyperpolarizes ASH through Galphao-dependent activation of IRK K+ channels. These results further emphasize that neuronal Ca2+ transients, as key reporters of neuronal depolarization, are also critical signaling intermediates in and of themselves, with multiple upstream inputs and downstream consequences.

Rachel Wragg et al. (2008) C.elegans Neuronal Development Meeting "Octopamine inhibits aversive responses to 30 and 100% octanol through two different G-protein coupled receptors"

Sarah Miller, Richard Komuniecki, Robert Steven, Lindsay Hughes, Rachel Wragg

[C.elegans Neuronal Development Meeting, 2008]

Nematodes lack an autonomic nervous system and epinephrine/norepinephine and instead appear to use tyramine (TA) and octopamine (OA) to modulate many key behaviors. In Caenorhabditis elegans distinct TA/OA neurons, receptors and behaviors have been identified. Previously, we demonstrated that OA abolishes 5-HT dependent increases in responses to dilute (30%) octanol through the G-protein coupled receptor, F14D12.6 (Wragg et al., 2007). The ASH sensory neurons are necessary and sufficient for detection of 30% octanol, and based on neuron-specific rescue, F14D12.6 appears to function in the ASHs to inhibit 5-HT mediated aversive responsiveness to dilute octanol. In contrast, the ADL and AWB sensory neurons in addition to the ASHs are all involved in the detection of 100% octanol (Chao et al., 2004). In the present study, we have demonstrated that OA inhibits aversive responses to 100% octanol in the presence or absence of food or 5-HT and this inhibition requires a different, previously uncharacterized, G-protein coupled receptor, Y54G2A.35, but not F14D12.6. OA inhibition in y54g2a.35(tm2104) null mutants can be restored by the expression of a full length y54g2a.35 transgene that includes 5 kb upstream of the predicted ATG. We have confirmed the WORMBASE prediction of the y54g2a.35 cDNA by RT-PCR. Interestingly, this cDNA predicts a receptor with an extremely short N-terminus that is most identical to mammalian alpha2A adrenergic receptors. Y54G2A.35 clusters with invertebrate OA receptors that couple to Galphaq. We are currently characterizing the pharmacology and coupling of Y54G2A.35 after heterologous expression in mammalian cells and Xenopus oocytes. Since two different OA receptors, F14D12.6 and Y54G2A.35 appear essential for OA inhibition of aversive responses to 30 and 100% octanol, respectively, future studies will focus on the identification of the specific neurons and signaling molecules involved in these two different pathways of OA inhibition. This work supported by NIH grant AI45147 to RWK.

Liu H et al. (2019) Proc Natl Acad Sci U S A "Reciprocal modulation of 5-HT and octopamine regulates pumping via feedforward and feedback circuits in C. elegans."

Li R, Al-Sheikh U, Qin LW, Liu H, Zhang C, Wu ZX

[Proc Natl Acad Sci U S A, 2019]

Feeding is vital for animal survival and is tightly regulated by the endocrine and nervous systems. To study the mechanisms of humoral regulation of feeding behavior, we investigated serotonin (5-HT) and octopamine (OA) signaling in <i>Caenorhabditis elegans</i>, which uses pharyngeal pumping to ingest bacteria into the gut. We reveal that a cross-modulation mechanism between 5-HT and OA, which convey feeding and fasting signals, respectively, mainly functions in regulating the pumping and secretion of both neuromodulators via ADF/RIC/SIA feedforward neurocircuit (consisting of ADF, RIC, and SIA neurons) and ADF/RIC/AWB/ADF feedback neurocircuit (consisting of ADF, RIC, AWB, and ADF neurons) under conditions of food supply and food deprivation, respectively. Food supply stimulates food-sensing ADFs to release more 5-HT, which augments pumping via inhibiting OA secretion by RIC interneurons and, thus, alleviates pumping suppression by OA-activated SIA interneurons/motoneurons. In contrast, nutrient deprivation stimulates RICs to secrete OA, which suppresses pumping via activating SIAs and maintains basal pumping and 5-HT production activity through excitation of ADFs relayed by AWB sensory neurons. Notably, the feedforward and feedback circuits employ distinct modalities of neurosignal integration, namely, disinhibition and disexcitation, respectively.

Agotegaray M et al. (2020) J Mater Sci Mater Med "-cyclodextrin coating: improving biocompatibility of magnetic nanocomposites for biomedical applications."

Blanco MG, Agotegaray M, Lassalle V, Massheimer V, Campelo A, Garcia E, De Rosa MJ, Zysler R

[J Mater Sci Mater Med, 2020]

The role Beta-cyclodextrin (CD) on improving biocompatibility on healthy cellular and animal models was studied upon a formulation obtained from the development of a simple coating procedure. The obtained nanosystems were thoroughly characterized by FTIR, TGA, atomic absorption spectroscopy, dynamic light scattering and zeta potential, TEM/HR-TEM and magnetic properties. CD might interact with the magnetic core through hosting OA. It is feasible that the nanocomposite is formed by nanoparticles of MG@OA dispersed in a CD matrix. The evaluation of CD role on biocompatibility was performed on two healthy models. To this end, in vivo studies were carried out on Caenorhabditis elegans. Locomotion and progeny were evaluated after exposure animals to MG, MG@OA, and MG@OA-CD (10 to 500g/mL). The influence of CD on cytotoxicity was explored in vitro on healthy rat aortic endothelial cells, avoiding alteration in the results derived from the use of transformed cell lines. Biological studies demonstrated that CD attaching improves MG biocompatibility.