Trude Marie Haug

• Golnarnik, Golnaz; Nieminen, Anni I.; Søland, Tine Merete; Galtung, Hilde & Haug, Trude M. (2026). Differential metabolic responses to hydrogen peroxide-induced oxidative stress in parotid and submandibular gland acinar cell lines. Biochemistry and Biophysics Reports. 46, p. 102596–102596. doi: 10.1016/j.bbrep.2026.102596. Full text in Research Archive
• Haugsten, Helene Rygvold; Kristoffersen, Anne Karin; Enersen, Morten; Thiede, Bernd; Søland, Tine Merete & Haug, Trude M. [Show all 7 contributors for this article] (2025). Bacterial extracellular vesicles from Porphyromonas gingivalis – proteomic profile and influence on oral fibroblasts. Archives of Oral Biology. ISSN 0003-9969. 181. doi: 10.1016/j.archoralbio.2025.106424. Full text in Research Archive Show summary

  Objectives In this study, we aimed to explore the protein content of bacterial extracellular vesicles (bEVs) from three strains of Porphyromonas gingivalis, an anaerobic gram-negative bacterium closely associated with periodontitis. Additionally, we aimed to investigate the effects of bEV uptake on human oral fibroblasts, to better understand the role of these vesicles in the pathogenesis of periodontitis. Design Liquid chromatography-mass spectrometry was performed on bEVs from three strains of P. gingivalis with different virulence: ATCC 33277, A7A1–28, and W83. Three key proteins associated with virulence were validated using dot blot. Proliferation and viability of human oral fibroblasts after incubation with bEVs were assessed at different timepoints and different concentrations of bEVs. Results A total of 307 proteins were identified in the bEVs from the three strains of P. gingivalis. Among those were several relevant for virulence, for example gingipains, fimbriae, and peptidyl-arginine deiminase (PPAD). When oral fibroblasts were exposed to bEVs from A7A1–28 or W83, proliferation was significantly affected after 12 and 24 h at one bEV concentration. Furthermore, viability was significantly affected by bEVs from W83 at several timepoints and bEV concentrations. bEVs from ATCC 33277 did not induce any significant changes. Conclusion Several proteins associated with virulence were detected in bEVs from all three strains of P. gingivalis, with varying abundance. Uptake of these bEVs can influence human cells, as exemplified by changes in viability and proliferation.

• Haugsten, Helene Rygvold; Lipka, Aleksandra Katarzyna; Kristoffersen, Anne Karin; Enersen, Morten; Nieminen, Anni & Søland, Tine Merete [Show all 8 contributors for this article] (2025). Metabolic Changes in Oral Fibroblasts After Exposure to Bacterial Extracellular Vesicles From Three Strains of Porphyromonas gingivalis. Cellular Microbiology. ISSN 1462-5814. 2025(1). doi: 10.1155/cmi/7515004. Full text in Research Archive Show summary

  Aims Porphyromonas gingivalis is a keystone pathogen in periodontitis that releases bacterial extracellular vesicles (bEVs) with a content derived from the membrane and cytosol of the bacteria itself. The bEVs are taken up by host tissue cells, such as oral fibroblasts, yet their effects on human cells remain incompletely understood. Methods The aim of this study was to investigate the impact of bEVs on human oral fibroblasts. Targeted liquid chromatography–mass spectrometry was used to assess changes in the metabolome of these cells following exposure to bEVs from three strains of P. gingivalis (ATCC 33277, A7A1-28, and W83). Metabolite content of the bEVs from each strain was also characterized. Result Metabolomic analyses revealed both common and strain-specific metabolites in the bEVs from these strains. Additionally, pathways mainly associated with amino acid metabolism were enriched for all. Following exposure to bEVs, the fibroblasts exhibited a metabolic shift in energy metabolism. In particular, fibroblasts incubated with bEVs from ATCC 33277 had a unique profile of enriched pathways after 10 min. However, after 24 h, this profile changed and became more similar to the profile in fibroblasts incubated with bEVs from the two more pathogenic strains. Pathway analysis revealed enrichment of glycerophospholipid and butanoate metabolism for fibroblasts exposed to all the bEVs. Additionally, altered sphingolipid metabolism was observed in fibroblasts following exposure to bEVs from ATCC 33277. Conclusion Our findings demonstrate that bEVs derived from P. gingivalis strains can induce changes in cellular processes in fibroblasts. This suggests a role of bEVs in the pathogenesis of periodontitis.

• Lipka, Aleksandra; Søland, Tine Merete; Nieminen, Anni I.; Sapkota, Dipak; Haug, Trude Marie & Galtung, Hilde (2025). The effect of extracellular vesicles derived from oral squamous cell carcinoma on the metabolic profile of oral fibroblasts. Frontiers in Molecular Biosciences. 12. doi: 10.3389/fmolb.2025.1492282. Full text in Research Archive Show summary

  Introduction: Oral cancer is one of the most common forms of head and neck cancers. Oral squamous cell carcinoma (OSCC) accounts for more than 90% of the oral malignancies. The molecular pathogenesis of OSCC is complex as it involves altered expression of specific genes and proteins, but also comprises changes in metabolic processes. It is suggested that extracellular vesicles (EVs) released by cancer cells may contribute to cancer development and metastasis by recruiting and changing phenotype of normal cells that surround the tumor. Methods: The aim of the project was to characterize the effect of OSCC EVs on the metabolic profile of normal oral fibroblasts (NOFs). Targeted liquid chromatography mass spectrometry metabolic profiling was performed on control cells and NOFs exposed to OSCC EVs for 24 and 48 h. Results: Analysis of detected metabolites revealed that OSCC EVs affected NOFs the most after 24 h of exposure. Among metabolites that were significantly altered at 24 h, pyruvate, ATP, UTP, coenzyme A, and dihydroxyacetone phosphate were upregulated, while fatty acids such as nervonic acid, linoleate, oleate, palmitoleic acid, and docosahexaenoic acid were downregulated. These findings were supported by Western blotting of pyruvate kinase M2 (PKM2) and aldolase, fructose-bisphosphate A (ALDOA). Conclusion: The metabolic pathways of glycolysis, citric acid cycle, and amino acid metabolism were enriched, suggesting that OSCC EVs cause phenotype switch in NOFs that may contribute to acquiring a pro-tumorigenic phenotype.

• Golnarnik, Golnaz; Thiede, Bernd; Søland, Tine Merete; Galtung, Hilde & Haug, Trude Marie (2025). Hydrogen peroxide-induced oxidative stress alters protein expression in two rat salivary acinar cell lines. Archives of Oral Biology. ISSN 0003-9969. 175. doi: 10.1016/j.archoralbio.2025.106254. Full text in Research Archive Show summary

  Objectives: This study aimed to investigate the impact of hydrogen peroxide-induced oxidative stress on the protein expression profiles of submandibular and parotid acinar cells using a proteomic approach. We sought to evaluate how oxidative stress might contribute to salivary gland dysfunction and whether the two glands respond differently.<p> <p>Design: Immortalized rat parotid gland (PG) and submandibular gland (SMG) acinar epithelial cell lines were exposed to 50 µM and 150 µM hydrogen peroxide for 24 hr, followed by protein identification and quantification via liquid chromatography-mass spectrometry. Immunofluorescence microscopy and western blot analysis validated selected protein expressions, and cell viability was assessed using trypan blue exclusion assays. <p>Results: Compared to controls, histone H4 expression increased in both cell types after hydrogen peroxide exposure, whereas voltage-dependent anion-selective channel 1, keratin 7, and keratin 8 increased only in parotid gland cells. Conversely, mitochondrial aldehyde dehydrogenase and kidney isoform glutaminase were downregulated in parotid gland cells. Basal expression of mitochondrial aldehyde dehydrogenase and catalase was higher in submandibular gland cells. At higher hydrogen peroxide concentrations, antioxidant proteins expression and cell viability were greater in submandibular gland cells compared to parotid gland cells. <p>Conclusions: Our results suggest that submandibular gland acinar cells exhibit greater resistance to oxidative stress compared to parotid gland cells, potentially due to distinct antioxidant and metabolic coping strategies. Understanding these gland-specific responses may contribute to future approaches to protect salivary glands from oxidative damage under pathological conditions.

• Golnarnik, Golnaz; Søland, Tine Merete; Galtung, Hilde & Haug, Trude Marie (2024). Hydrogen peroxide disrupts the regulatory pathway of saliva secretion in two salivary acinar rat cell lines. Frontiers in Molecular Biosciences. 11. doi: 10.3389/fmolb.2024.1480721. Full text in Research Archive Show summary

  Background: Secretion of saliva is controlled by autonomic nerve signals via regulation of Ca2+-dependent ion transport across acinar cell membranes. Oxidative stress may affect this process, leading to a decrease in saliva production. This study investigates elements of the Ca2+ regulatory pathway and their vulnerability to hydrogen peroxide-induced oxidative stress. Methods: Rat parotid and submandibular salivary gland acinar cell lines were exposed to different hydrogen peroxide concentrations to simulate oxidative stress. Cell viability and intracellular reactive oxygen species were measured, mRNA levels were assessed via RT-qPCR, and protein expression was studied using western blot and immunofluorescence microscopy. Results: Elevated concentrations of hydrogen peroxide reduced cell viability and increased intracellular levels of reactive oxygen species and led to a decrease in cholinergic receptor muscarinic 3 and adrenoreceptor alpha 1A mRNA and protein levels in both cell lines. In parotid gland cells, both mRNA and protein levels of stromal interaction molecule 1 and Orai1 decreased with increasing concentrations of hydrogen peroxide. In contrast, in submandibular gland cells stromal interaction molecule 1 and Orai1 displayed differential mRNA and protein expression levels. Conclusion: Our study revealed that hydrogen peroxide exposure alters rat parotid and submandibular acinar cells, increasing reactive oxygen species and reducing autonomic receptor expression. Differential mRNA and protein expression of stromal interaction molecule 1 and Orai1 highlight complex oxidative stress effects on Ca2⁺ signaling. Most likely these effects will be deleterious to salivary secretion, but some effects may be protective.

• Søland, Tine Merete; Lipka, Aleksandra Katarzyna; Ruus, Ann-Kristin; Molværsmyr, Ann-Kristin; Galtung, Hilde & Haug, Trude Marie (2024). Extracellular vesicles from cancer cell lines of different origins drive the phenotype of normal oral fibroblasts in a CAF-like direction. Frontiers in Oncology. 14. doi: 10.3389/fonc.2024.1456346. Full text in Research Archive Show summary

  Introduction: Normal oral fibroblasts (NOFs) are located in the connective tissue of the oral mucosa. The NOFs play an important role in wound healing, tumor progression, and metastasis. They are subjected to influence by external and internal stimuli, among them extracellular vesicles (EVs), that are considered as important players in cell to cell communication, especially in carcinogenesis and metastatic processes. During tumorigenesis, stromal NOFs may undergo activation into cancer-associated fibroblasts (CAFs) that modify their phenotype to provide pro-oncogenic signals that in turn facilitate tumor initiation, progression, and metastasis. The aim of the study was to reveal the effect of EVs derived from local (oral squamous cell carcinoma – OSCC) and distant (pancreatic adenocarcinoma – PDAC; malignant melanoma brain metastasis – MBM) cancer origin on NOFs and their possible change into a CAF-like direction. Methods: The effect of each of the cancer EV types on NOFs proliferation, viability, and migration was tested. Also, changes in gene expression of the well-established CAF biomarkers ACTA2, FAP, PDGFR, and two putative CAF biomarkers, the Ca2+- activated ion channels ANO1 and KCNMA, were studied. Results: Obtained results indicate that NOFs receive and process signals transmitted by EVs originating from both OSCC, PDAC, and MBM. The fibroblast response was dependent on EV origin and concentration, and duration of EV exposure. Conclusion: The present results indicate that the molecular cargo of the EVs direct NOFs towards a pro-tumorigenic phenotype.

• Haugsten, Helene Rygvold; Kristoffersen, Anne Karin; Haug, Trude Marie; Søland, Tine Merete; Øvstebø, Reidun & Aass, Hans Christian [Show all 8 contributors for this article] (2023). Isolation, characterization, and fibroblast uptake of bacterial extracellular vesicles from Porphyromonas gingivalis strains. MicrobiologyOpen. 12(5). doi: 10.1002/mbo3.1388. Full text in Research Archive Show summary

  Periodontitis is an inflammatory condition caused by bacteria and represents a serious health problem worldwide as the inflammation damages the supporting tissues of the teeth and may predispose to systemic diseases. Porphyromonas gingivalis is considered a keystone periodontal pathogen that releases bacterial extracellular vesicles (bEVs) containing virulence factors, such as gingipains, that may contribute to the pathogenesis of periodontitis. This study aimed to isolate and characterize bEVs from three strains of P. gingivalis, investigate putative bEV uptake into human oral fibroblasts, and determine the gingipain activity of the bEVs. bEVs from three bacterial strains, ATCC 33277, A7A1-28, and W83, were isolated through ultrafiltration and size-exclusion chromatography. Vesicle size distribution was measured by nano-tracking analysis (NTA). Transmission electron microscopy was used for bEV visualization. Flow cytometry was used to detect bEVs and gingipain activity was measured with an enzyme assay using a substrate specific for arg-gingipain. The uptake of bEVs into oral fibroblasts was visualized using confocal microscopy. NTA showed bEV concentrations from 108 to 1011 particles/mL and bEV diameters from 42 to 356 nm. TEM pictures demonstrated vesicle-like structures. bEV-gingipains were detected both by flow cytometry and enzyme assay. Fibroblasts incubated with bEVs labeled with fluorescent dye displayed intracellular localization consistent with bEV internalization. In conclusion, bEVs from P. gingivalis were successfully isolated and characterized, and their uptake into human oral fibroblasts was documented. The bEVs displayed active gingipains demonstrating their origin from P. gingivalis and the potential role of bEVs in periodontitis.

• Grønlien, Heidi Kristine; Fontaine, Romain; Hodne, Kjetil; Tysseng, Linn Isabelle; Ager-Wick, Eirill & Weltzien, Finn-Arne [Show all 7 contributors for this article] (2021). Long extensions with varicosity-like structures in gonadotrope Lh cells facilitate clustering in medaka pituitary culture. PLOS ONE. 16(1). doi: 10.1371/journal.pone.0245462. Full text in Research Archive Show summary

  Accumulating evidence indicates that some pituitary cell types are organized in complex networks in both mammals and fish. In this study, we have further investigated the previously described cellular extensions formed by the medaka ( Oryzias latipes ) luteinizing hormone gonadotropes (Lh cells). Extensions, several cell diameters long, with varicosity-like swellings, were common both in vitro and in vivo . Some extensions approached other Lh cells, while others were in close contact with blood vessels in vivo . Gnrh further stimulated extension development in vitro . Two types of extensions with different characteristics could be distinguished, and were classified as major or minor according to size, origin and cytoskeleton protein dependance. The varicosity-like swellings appeared on the major extensions and were dependent on both microtubules and actin filaments. Immunofluorescence revealed that Lhβ protein was mainly located in these swellings and at the extremity of the extensions. We then investigated whether these extensions contribute to network formation and clustering, by following their development in primary cultures. During the first two days in culture, the Lh cells grew long extensions that with time physically attached to other cells. Successively, tight cell clusters formed as cell somas that were connected via extensions migrated towards each other, while shortening their extensions. Laser photolysis of caged Ca 2+ showed that Ca 2+ signals originating in the soma propagated from the soma along the major extensions, being particularly visible in each swelling. Moreover, the Ca 2+ signal could be transferred between densely clustered cells (sharing soma-soma border), but was not transferred via extensions to the connected cell. In summary, Lh gonadotropes in medaka display a complex cellular structure of hormone-containing extensions that are sensitive to Gnrh, and may be used for clustering and possibly hormone release, but do not seem to contribute to communication between cells themselves.

• Ciani, Elia; Haug, Trude M; Maugars, Gersende Marie Aimee; Weltzien, Finn-Arne; Falcón, Jack & Fontaine, Romain (2021). Effects of Melatonin on Anterior Pituitary Plasticity: A Comparison Between Mammals and Teleosts. Frontiers in Endocrinology. 11, p. 1–20. doi: 10.3389/fendo.2020.605111. Full text in Research Archive Show summary

  Melatonin is a key hormone involved in the photoperiodic signaling pathway. In both teleosts and mammals, melatonin produced in the pineal gland at night is released into the blood and cerebrospinal fluid, providing rhythmic information to the whole organism. Melatonin acts via specific receptors, allowing the synchronization of daily and annual physiological rhythms to environmental conditions. The pituitary gland, which produces several hormones involved in a variety of physiological processes such as growth, metabolism, stress and reproduction, is an important target of melatonin. Melatonin modulates pituitary cellular activities, adjusting the synthesis and release of the different pituitary hormones to the functional demands, which changes during the day, seasons and life stages. It is, however, not always clear whether melatonin acts directly or indirectly on the pituitary. Indeed, melatonin also acts both upstream, on brain centers that control the pituitary hormone production and release, as well as downstream, on the tissues targeted by the pituitary hormones, which provide positive and negative feedback to the pituitary gland. In this review, we describe the known pathways through which melatonin modulates anterior pituitary hormonal production, distinguishing indirect effects mediated by brain centers from direct effects on the anterior pituitary. We also highlight similarities and differences between teleosts and mammals, drawing attention to knowledge gaps, and suggesting aims for future research.

• Berntsen, Hanne Friis; Moldes-Anaya, Angel; Bjørklund, Cesilie Granum; Ragazzi, Lorenzo; Haug, Trude M & Strandabø, Rønnaug [Show all 10 contributors for this article] (2020). Perfluoroalkyl acids potentiate glutamate excitotoxicity in rat cerebellar granule neurons. Toxicology. ISSN 0300-483X. 445. doi: 10.1016/j.tox.2020.152610. Full text in Research Archive Show summary

  Perfluoroalkyl acids (PFAAs) are persistent man-made chemicals, ubiquitous in nature and present in human samples. Although restrictions are being introduced, they are still used in industrial processes as well as in consumer products. PFAAs cross the blood-brain-barrier and have been observed to induce adverse neurobehavioural effects in humans and animals as well as adverse effects in neuronal in vitro studies. The sulfonated PFAA perfluorooctane sulfonic acid (PFOS), has been shown to induce excitotoxicity via the N-methyl-D-aspartate receptor (NMDA-R) in cultures of rat cerebellar granule neurons (CGNs). In the present study the aim was to further characterise PFOS-induced toxicity (1–60 μM) in rat CGNs, by examining interactions between PFOS and elements of glutamatergic signalling and excitotoxicity. Effects of the carboxylated PFAA, perfluorooctanoic acid (PFOA, 300–500 μM) on the same endpoints were also examined. During experiments in immature cultures at days in vitro (DIV) 8, PFOS increased both the potency and efficacy of glutamate, whereas in mature cultures at DIV 14 only increased potency was observed. PFOA also increased potency at DIV 14. PFOS-enhanced glutamate toxicity was further antagonised by the competitive NMDA-R antagonist 3-((R)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) at DIV 8. At DIV 8, PFOS also induced glutamate release (9–13 fold increase vs DMSO control) after 1−3 and 24 h exposure, whereas for PFOA a large (80 fold) increase was observed, but only after 24 h. PFOS and PFOA both also increased alanine and decreased serine levels after 24 h exposure. In conclusion, our results indicate that PFOS at concentrations relevant in an occupational setting, may be inducing excitotoxicity, and potentiation of glutamate signalling, via an allosteric action on the NMDA-R or by actions on other elements regulating glutamate release or NMDA-R function. Our results further support our previous findings that PFOS and PFOA at equipotent concentrations induce toxicity via different mechanisms of action.

• Tennøe, Simen; Hodne, Kjetil; Haug, Trude; Weltzien, Finn-Arne; Einevoll, Gaute & Halnes, Geir (2019). [Re] Fast-Activating Voltage- and Calcium-Dependent Potassium (BK) Conductance Promotes Bursting in Pituitary Cells: A Dynamic Clamp Study. ReScience. ISSN 2430-3658. 5(1). doi: 10.5281/zenodo.2611252. Full text in Research Archive
• Halnes, Geir; Tennøe, Simen; Haug, Trude; Einevoll, Gaute; Weltzien, Finn-Arne & Hodne, Kjetil (2019). A computational model for gonadotropin releasing cells in the teleost fish medaka. PLoS Computational Biology. ISSN 1553-734X. 15(8), p. 1–28. doi: 10.1371/journal.pcbi.1006662. Full text in Research Archive Show summary

  Pituitary endocrine cells fire action potentials (APs) to regulate their cytosolic Ca2+ concentration and hormone secretion rate. Depending on animal species, cell type, and biological conditions, pituitary APs are generated either by TTX-sensitive Na+ currents (INa), high-voltage activated Ca2+ currents (ICa), or by a combination of the two. Previous computational models of pituitary cells have mainly been based on data from rats, where INa is largely inactivated at the resting potential, and spontaneous APs are predominantly mediated by ICa. Unlike in rats, spontaneous INa-mediated APs are consistently seen in pituitary cells of several other animal species, including several species of fish. In the current work we develop a computational model of gonadotropin releasing cells in the teleost fish medaka (Oryzias latipes). The model stands out from previous modeling efforts by being (1) the first model of a pituitary cell in teleosts, (2) the first pituitary cell model that fires sponateous APs that are predominantly mediated by INa, and (3) the first pituitary cell model where the kinetics of the depolarizing currents, INa and ICa, are directly fitted to voltage-clamp data. We explore the firing properties of the model, and compare it to the properties of previous models that fire ICa-based APs. We put a particular focus on how the big conductance K+ current (IBK) modulates the AP shape. Interestingly, we find that IBK can prolong AP duration in models that fire ICa-based APs, while it consistently shortens the duration of the predominantly INa-mediated APs in the medaka gonadotroph model. Although the model is constrained to experimental data from gonadotroph cells in medaka, it may likely provide insights also into other pituitary cell types that fire INa-mediated APs.

• Krogh, Kristine von; Bjørndal, Gunnveig Toft; Nourizadeh-Lillabadi, Rasoul; Ropstad, Erik; Haug, Trude & Weltzien, Finn-Arne (2019). Cortisol differentially affects cell viability and reproduction-related gene expression in Atlantic cod pituitary cultures dependent on stage of sexual maturation. Comparative Biochemistry and Physiology A. ISSN 1095-6433. 236. doi: 10.1016/j.cbpa.2019.06.017. Full text in Research Archive Show summary

  Through the action of cortisol, stress can affect reproductive biology with behavioural and physiological alterations. Using mixed sex primary pituitary cultures from Atlantic cod (Gadus morhua), the present study aimed to investigate potential direct effects of basal and stress level cortisol on the pituitary in terms of cell viability and reproduction-related gene expression at different stages of sexual maturity. Stress level of cortisol stimulated cell viability in cells derived from sexually maturing and mature fish. In cells from spent fish, high cortisol levels did not affect cell viability in terms of metabolic activity, but did stimulate viability in terms of membrane integrity. Basal cortisol levels did not affect cell viability. Ethanol, used as solvent for cortisol, decreased cell viability at all maturity stages, but did generally not affect gene expression. Genes investigated were fshb, lhb and two Gnrh receptors expressed in cod gonadotropes (gnrhr1b and gnrhr2a). Cortisol had dual effects on fshb expression; stimulating expression in cells from mature fish at stress dose, while inhibiting expression in cells from spent fish at both doses. In contrast, cortisol had no direct effect on lhb expression. While gnrhr2a transcript levels largely increased following cortisol treatment, gnrhr1b expression decreased in cells from spent fish and was unaffected at other maturity stages. These findings demonstrate that cortisol can act directly and differentially at the pituitary level in Atlantic cod and that factors facilitating these actions are dose-dependently activated and vary with level of sexual maturity.

• Krogh, Kristine von; Ropstad, Erik; Nourizadeh-Lillabadi, Rasoul; Haug, Trude & Weltzien, Finn-Arne (2019). In Vitro Effects of Bisphenol A and Tetrabromobisphenol A on Cell Viability and Reproduction-Related Gene Expression in Pituitaries from Sexually Maturing Atlantic Cod (Gadus morhua L.). Fishes. 4(3). doi: 10.3390/fishes4030048. Full text in Research Archive Show summary

  Bisphenol A (BPA) and tetrabromobisphenol A (TBBPA) are widely used industrial chemicals, ubiquitously present in the environment. While BPA is a well-known endocrine disruptor and able to affect all levels of the teleost reproductive axis, information regarding TBBPA on this subject is very limited. Using primary cultures from Atlantic cod (Gadus morhua), the present study was aimed at investigating potential direct effects of acute (72 h) BPA and TBBPA exposure on cell viability and the expression of reproductive-relevant genes in the pituitary. The results revealed that both bisphenols stimulate cell viability in terms of metabolic activity and membrane integrity at environmentally relevant concentrations. BPA had no direct effects on gonadotropin gene expression, but enhanced the expression of gonadotropin-releasing hormone (GnRH) receptor 2a, the main gonadotropin modulator in Atlantic cod. In contrast, TBBPA increased gonadotropin transcript levels but had no effect on GnRH receptor mRNA. In conclusion, both anthropogenic compounds display endocrine disruptive properties and are able to directly interfere with gene expression related to reproductive function in cod pituitary cells at environmentally relevant concentrations in vitro.

• Fontaine, Romain David; Ciani, Elia; Haug, Trude M; Hodne, Kjetil; Ager-Wick, Eirill & Baker, Dianne [Show all 7 contributors for this article] (2019). Gonadotrope plasticity at cellular, population and structural levels: A comparison between fishes and mammals. General and Comparative Endocrinology. ISSN 0016-6480. 287, p. 1–20. doi: 10.1016/j.ygcen.2019.113344. Full text in Research Archive Show summary

  Often referred to as “the master gland”, the pituitary is a key organ controlling growth, maturation, and homeostasis in vertebrates. The anterior pituitary, which contains several hormone-producing cell types, is highly plastic and thereby able to adjust the production of the hormones governing these key physiological processes according to the changing needs over the life of the animal. Hypothalamic neuroendocrine control and feedback from peripheral tissues modulate pituitary cell activity, adjusting levels of hormone production and release according to different functional or environmental requirements. However, in some physiological processes (e.g. growth, puberty, or metamorphosis), changes in cell activity may be not sufficient to meet the needs and a general reorganization of cell composition and pituitary structure may occur. Focusing on gonadotropes, this review examines plasticity at the cellular level, which allows precise and rapid control of hormone production and secretion, as well as plasticity at the population and structural levels, which allows more substantial changes in hormone production. Further, we compare current knowledge of the anterior pituitary plasticity in fishes and mammals in order to assess what has been conserved or not throughout evolution, and highlight important remaining questions.

• Berntsen, Hanne Friis; Bjørklund, Cesilie Granum; Strandabø, Rønnaug; Haug, Trude; Moldes-Anaya, Angel & Fuentes-Lazaro, Judit [Show all 10 contributors for this article] (2018). PFOS-induced excitotoxicity is dependent on Ca2+ influx via NMDA receptors in rat cerebellar granule neurons. Toxicology and Applied Pharmacology. ISSN 0041-008X. 357, p. 19–32. doi: 10.1016/j.taap.2018.08.015. Full text in Research Archive Show summary

  Perfluoroalkyl acids (PFAAs) are persistent compounds used in many industrial as well as consumer products. Despite restrictions, these compounds are found at measurable concentrations in samples of human and animal origin. In the present study we examined whether the effects on cell viability of two sulfonated and four carboxylated PFAAs in cultures of cerebellar granule neurons (CGNs), could be associated with deleterious activation of the N-methyl-d-aspartate receptor (NMDA-R). PFAA-induced effects on viability in rat CGNs and unstimulated PC12 cells were examined using the MTT assay. Cells from the PC12 rat pheochromocytoma cell line lack the expression of functional NMDA-Rs and were used to verify lower toxicity of perfluorooctanesulfonic acid (PFOS) in cells not expressing NMDA-Rs. Protective effects of NMDA-R antagonists, and extracellular as well as intracellular Ca2+ chelators were investigated. Cytosolic Ca2+ ([Ca2+]i) was measured using Fura-2. In rat CGNs the effects of the NMDA-R antagonists MK-801, memantine and CPP indicated involvement of the NMDA-R in the decreased viability induced by PFOS and perfluorohexanesulfonic acid (PFHxS). No effects were associated with the four carboxylated PFAAs studied. Further, EGTA and CPP protected against PFOS-induced decreases in cell viability, whereas no protection was afforded by BAPTA-AM. [Ca2+]i significantly increased after exposure to PFOS, and this increase was completely blocked by MK-801. In PC12 cells a higher concentration of PFOS was required to induce equivalent levels of toxicity as compared to in rat CGNs. PFOS-induced toxicity in PC12 cells was not affected by CPP. In conclusion, PFOS at the tested concentrations induces excitotoxicity in rat CGNs, which likely involves influx of extracellular Ca2+ via the NMDA-R. This effect can be blocked by specific NMDA-R antagonists.

• Ager-Wick, Eirill; Hodne, Kjetil; Fontaine, Romain; Krogh, Kristine von; Haug, Trude & Weltzien, Finn-Arne (2018). Preparation of a High-quality Primary Cell Culture from Fish Pituitaries. Journal of Visualized Experiments. 2018(138). doi: 10.3791/58159. Full text in Research Archive Show summary

  Primary cell culture is a powerful tool commonly used by scientists to study cellular properties and mechanisms of isolated cells in a controlled environment. Despite vast differences in the physiology between mammals and fish, primary cell culture protocols from fish are often based on mammalian culture conditions, often with only minor modifications. The environmental differences affect not only body temperature, but also blood serum parameters such as osmolality, pH, and pH buffer capacity. As cell culture media and similar working solutions are meant to mimic characteristics of the extracellular fluid and/or blood serum to which a cell is adapted, it is crucial that these parameters are adjusted specifically to the animal in question. The current protocol describes optimized primary culture conditions for medaka (Oryzias latipes). The protocol provides detailed steps on how to isolate and maintain healthy dissociated pituitary cells for more than one week and includes the following steps: 1. the adjustment of the osmolality to the values found in medaka blood plasma, 2. the adjustment of the incubation temperature to normal medaka temperature (here in the aquarium facility), and 3. the adjustment of the pH and bicarbonate buffer to values comparable to other fish species living at similar temperatures. The results presented using the described protocol promote physiologically meaningful results for medaka and can be used as a reference guide by scientists making primary cell cultures from other non-mammalian species.

• Krogh, Kristine von; Bjørndal, Gunnveig Toft; Nourizadeh-Lillabadi, Rasoul; Hodne, Kjetil; Ropstad, Erik & Haug, Trude M [Show all 7 contributors for this article] (2017). Sex steroids differentially regulate fshb, lhb and gnrhr expression in Atlantic cod (Gadus morhua). Reproduction. ISSN 1470-1626. 154(5), p. 581–594. doi: 10.1530/REP-17-0208. Full text in Research Archive
• Strandabø, Rønnaug; Grønlien, Heidi Kristine; Ager-Wick, Eirill; Nourizadeh-Lillabadi, Rasoul; Hildahl, Jon Paul & Weltzien, Finn-Arne [Show all 7 contributors for this article] (2016). Identified lhb-expressing cells from medaka (Oryzias latipes) show similar Ca2+-response to all endogenous Gnrh forms, and reveal expression of a novel fourth Gnrh receptor. General and Comparative Endocrinology. ISSN 0016-6480. 229, p. 19–31. doi: 10.1016/j.ygcen.2016.02.019. Full text in Research Archive
• Ager-Wick, Eirill; Henkel, Christian W.; Haug, Trude M & Weltzien, Finn-Arne (2014). Using normalization to resolve RNA-seq biases caused by amplification from minimal input. Physiological Genomics. ISSN 1094-8341. 46(21), p. 808–820. doi: 10.1152/physiolgenomics.00196.2013. Full text in Research Archive Show summary

  RNA-Seq has become a widely used method to study transcriptomes, and it is now possible to perform RNA-Seq on almost any sample. Nevertheless, samples obtained from small cell populations are particularly challenging, as biases associated with low amounts of input RNA can have strong and detrimental effects on downstream analyses. Here we compare different methods to normalize RNA-Seq data obtained from minimal input material. Using RNA from isolated medaka pituitary cells, we have amplified material from six samples before sequencing. Both synthetic and real data are used to evaluate different normalization methods to obtain a robust and reliable pipeline for analysis of RNA-Seq data from samples with very limited input material. The analysis outlined here shows that quantile normalization outperforms other more commonly used normalization procedures when using amplified RNA as input and will benefit researchers employing low amounts of RNA in similar experiments.

• Sandvik, Guro Katrine; Hodne, Kjetil; Haug, Trude M; Okubo, Kataaki & Weltzien, Finn-Arne (2014). RFamide peptides in early vertebrate development. Frontiers in Endocrinology. 5:203. doi: 10.3389/fendo.2014.00203. Full text in Research Archive
• Weltzien, Finn-Arne; Hildahl, Jon Paul; Hodne, Kjetil; Okubo, Kataaki & Haug, Trude M (2014). Embryonic development of gonadotrope cells and gonadotropic hormones - Lessons from model fish. Molecular and Cellular Endocrinology. ISSN 0303-7207. 385, p. 18–27. doi: 10.1016/j.mce.2013.10.016. Full text in Research Archive
• Weltzien, Finn-Arne; Hildahl, Jon Paul; Hodne, Kjetil; Okubo, Kataaki & Haug, Trude M (2014). Embryonic development of gonadotrope cells and gonadotropic hormones - Lessons from model fish. Molecular and Cellular Endocrinology. ISSN 0303-7207. 385(1-2), p. 18–27. doi: 10.1016/j.mce.2013.10.016. Full text in Research Archive
• Sand, Sverre; Nissen-Meyer, Jon; Sand, Olav & Haug, Trude M (2013). Plantaricin A, a cationic peptide produced by Lactobacillus plantarum, permeabilizes eukaryotic cell membranes by a mechanism dependent on negative surface charge linked to glycosylated membrane proteins. Biochimica et Biophysica Acta - Biomembranes. ISSN 0005-2736. 1828(2), p. 249–259. doi: 10.1016/j.bbamem.2012.11.001. Full text in Research Archive
• Hodne, Kjetil; Strandabø, Rønnaug; Krogh, Kristine von; Nourizadeh-Lillabadi, Rasoul; Sand, Olav & Weltzien, Finn-Arne [Show all 7 contributors for this article] (2013). Electrophysiological differences between fshb- and lhb-expresing gonadotropes in primary culture. Endocrinology. ISSN 0013-7227. 154(9), p. 3319–3330. doi: 10.1210/en.2013-1164. Full text in Research Archive
• Mobråten, Kaia; Haug, Trude M; Kleiveland, Charlotte Ramstad & Lea, Tor Erling (2013). Omega-3 and omega-6 PUFAs induce the same GPR120-mediated signalling events, but with different kinetics and intensity in Caco-2 cells. Lipids in Health and Disease. 12. doi: 10.1186/1476-511X-12-101. Full text in Research Archive Show summary

  Background Omega-3 PUFAs are known to have anti-inflammatory properties, and different mechanisms are involved. GPR120 is a G-protein coupled receptor that has recently received attention because of its anti-inflammatory signalling properties after binding omega-3 PUFAs. However, both omega-3 and omega-6 PUFAs are natural GPR120 ligands. The aim of this study was to study possible differences in GPR120-mediated signalling events after treatment with different long-chain PUFAs in intestinal epithelial cells. We also investigated possible GPR120-mediated anti-inflammatory effects of different long-chain PUFAs that may be relevant in the understanding of how dietary PUFAs influence inflammatory responses in inflammatory diseases such as IBD. Methods We used Caco-2 cells as a model system to study GPR120-mediated signalling events because we found this cell line to express GPR120, but not GPR40, another plasma membrane receptor for medium- and long chain fatty acids. Increase in cytosolic Ca2+concentration, activation of MAP kinase ERK1/2 and the inhibition of IL-1β induced NF-κB activity were studied to reveal potential differences in the activation of GPR120 by the omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the omega-6 PUFA arachidonic acid (AA). Results We found that EPA, DHA and AA enhanced the cytosolic concentration of the second messenger Ca2+ with the same efficiency, but with different kinetics. Both omega-3 and omega-6 PUFAs activated MAP kinase ERK1/2, but differences regarding kinetics and intensity were also observed in this pathway. ERK1/2 activation was shown to be dependent upon EGFR and Raf-1. We further investigated the ability of EPA, DHA and AA to inhibit NF-κB activity in Caco-2 cells. All PUFAs tested were able to inhibit IL-1β induced breakdown of IκBα after binding to GPR120, but with different potency. Conclusions Our results show that EPA, DHA and AA elicit the same signalling events, but with different kinetics and efficiency through GPR120 in Caco-2 cells. We show, for the first time, that both omega-3 and omega-6 PUFAs inhibit NF-κB activation in intestinal epithelial cells. Our results may be important for understanding how dietary PUFAs influence inflammatory processes relevant in delineating effects of PUFAs in the treatment of IBD.

• Hildahl, Jon Paul; Taranger, Geir Lasse; Norberg, Birgitta; Haug, Trude M & Weltzien, Finn-Arne (2013). Differential regulation of GnRH ligand and receptor genes in the brain and pituitary of Atlantic cod exposed to different photoperiod. General and Comparative Endocrinology. ISSN 0016-6480. 180, p. 7–14. doi: 10.1016/j.ygcen.2012.09.025. Full text in Research Archive
• Strandabø, Rønnaug; Hodne, Kjetil; Ager-Wick, Eirill; Sand, Olav; Weltzien, Finn-Arne & Haug, Trude M (2013). Signal transduction involved in GnRH2-stimulation of identified LH-producing gonadotropes from lhb-GFP transgenic medaka (Oryzias latipes). Molecular and Cellular Endocrinology. ISSN 0303-7207. 372(1-2), p. 128–139. doi: 10.1016/j.mce.2013.03.022. Full text in Research Archive
• Hodne, Kjetil; Krogh, Kristine von; Weltzien, Finn-Arne; Sand, Olav & Haug, Trude M (2012). Optimized conditions for primary culture of pituitary cells from the Atlantic cod (Gadus morhua). The importance of osmolality, pCO(2), and pH. General and Comparative Endocrinology. ISSN 0016-6480. 178(2), p. 206–215. doi: 10.1016/j.ygcen.2012.06.005. Full text in Research Archive
• Hildahl, Jon Paul; Sandvik, Guro Katrine; Lifjeld, Rikke; Hodne, Kjetil; Nagahama, Y & Haug, Trude M [Show all 8 contributors for this article] (2012). Developmental Tracing of Luteinizing Hormone b-Subunit Gene Expression Using Green Fluorescent Protein Transgenic Medaka (Oryzias latipes) Reveals a Putative Novel Developmental Function. Developmental Dynamics. ISSN 1058-8388. 241(11), p. 1665–1677. doi: 10.1002/dvdy.23860. Full text in Research Archive
• Hildahl, Jon; Sandvik, Guro Katrine; Edvardsen, Rolf; Norberg, Birgitta; Haug, Trude M & Weltzien, Finn-Arne (2011). Four gonadotropin releasing hormone receptor genes in Atlantic cod are differentially expressed in the brain and pituitary during puberty. General and Comparative Endocrinology. ISSN 0016-6480. 173(2), p. 333–345. doi: 10.1016/j.ygcen.2011.06.002. Full text in Research Archive
• Hildahl, Jon; Sandvik, Guro Katrine; Edvardsen, Rolf; Fagernes, Cathrine Elisabeth; Norberg, Birgitta & Haug, Trude M [Show all 7 contributors for this article] (2011). Identification and gene expression analysis of three GnRH genes in female Atlantic cod during puberty provides insight into GnRH variant gene loss in fish. General and Comparative Endocrinology. ISSN 0016-6480. 172(3), p. 458–467. doi: 10.1016/j.ygcen.2011.04.010. Full text in Research Archive
• Andersland, Kristin; Jølle, Guro Five; Sand, Olav & Haug, Trude M (2010). Peptide Pheromone Plantaricin A Produced by Lactobacillus plantarum Permeabilizes Liver and Kidney Cells. Journal of Membrane Biology. ISSN 0022-2631. 235(2), p. 121–129. doi: 10.1007/s00232-010-9263-4. Full text in Research Archive
• Hodne, Kjetil; Haug, Trude M & Weltzien, Finn-Arne (2010). Single-cell qPCR on dispersed primary pituitary cells -an optimized protocol. BMC Molecular Biology. 11. doi: 10.1186/1471-2199-11-82. Full text in Research Archive Show summary

  Background The incidence of false positives is a potential problem in single-cell PCR experiments. This paper describes an optimized protocol for single-cell qPCR measurements in primary pituitary cell cultures following patch-clamp recordings. Two different cell harvesting methods were assessed using both the GH4 prolactin producing cell line from rat, and primary cell culture from fish pituitaries. Results Harvesting whole cells followed by cell lysis and qPCR performed satisfactory on the GH4 cell line. However, harvesting of whole cells from primary pituitary cultures regularly produced false positives, probably due to RNA leakage from cells ruptured during the dispersion of the pituitary cells. To reduce RNA contamination affecting the results, we optimized the conditions by harvesting only the cytosol through a patch pipette, subsequent to electrophysiological experiments. Two important factors proved crucial for reliable harvesting. First, silanizing the patch pipette glass prevented foreign extracellular RNA from attaching to charged residues on the glass surface. Second, substituting the commonly used perforating antibiotic amphotericin B with β-escin allowed efficient cytosol harvest without loosing the giga seal. Importantly, the two harvesting protocols revealed no difference in RNA isolation efficiency. Conclusion Depending on the cell type and preparation, validation of the harvesting technique is extremely important as contaminations may give false positives. Here we present an optimized protocol allowing secure harvesting of RNA from single cells in primary pituitary cell culture following perforated whole cell patch clamp experiments.

• Haug, Trude Marie; Sand, Sverre; Sand, Olav; Phung, Danh; Granum, Per Einar & Hardy, Simon P. (2010). Formation of Very Large Conductance Channels by Bacillus cereus Nhe in Vero and GH4 Cells Identifies NheA + B as the Inherent Pore-Forming Structure. Journal of Membrane Biology. ISSN 0022-2631. 237, p. 1–11. Full text in Research Archive
• Haug, Trude M; Sand, Sverre; Sand, Olav; Phung, Danh; Granum, Per Einar & Hardy, Simon P. (2010). Formation of Very Large Conductance Channels by Bacillus cereus Nhe in Vero and GH(4) Cells Identifies NheA plus B as the Inherent Pore-Forming Structure. Journal of Membrane Biology. ISSN 0022-2631. 237(1), p. 1–11. doi: 10.1007/s00232-010-9298-6. Full text in Research Archive
• Haug, Trude M; Hodne, Kjetil; Weltzien, Finn-Arne & Sand, Olav (2007). Electrophysiological properties of pituitary cells in primary culture from Atlantic cod (Gadus morhua). Neuroendocrinology. ISSN 0028-3835. 86, p. 38–47. doi: 10.1159/000103867. Full text in Research Archive
• Sand, Sverre; Haug, Trude M; Nissen-Meyer, Jon & Sand, Olav (2007). The bacterial peptide pheromone plantaricin a permeabilizes cancerous, but not normal, rat pituitary cells and differentiates between the outer and inner membrane leaflet. Journal of Membrane Biology. ISSN 0022-2631. 216(2-3), p. 61–71. doi: 10.1007/s00232-007-9030-3. Full text in Research Archive
• Hafting, Torkel; Haug, Trude M; Ellefsen, Stian & Sand, Olav (2006). Hypotonic stress activates BK channels in clonal kidney cells via purinergic receptors, presumably of the P2Y1 subtype. Acta Physiologica. ISSN 1748-1708. 188(1), p. 21–32. doi: 10.1111/j.1748-1716.2006.01601. Full text in Research Archive
• Mørk, Halvor Kjeang; Haug, Trude M & Sand, Olav (2005). Contribution of different Ca-activated K channels to the first phase of the response to TRH in clonal rat anterior pituitary cells. Acta Physiologica Scandinavica. ISSN 0001-6772. 184(2), p. 141–150. doi: 10.1111/j.1365-201X.2005.01441. Full text in Research Archive
• Haug, Trude M; Sigg, D; Ciani, S; Toro, L; Stefani, E & Olcese, R (2004). Regulation of K+ flow by a ring of negative charges in the outer pore of the BKCa channels. Part I: Aspartate 292 modulates K+ conductance by external surface charge effect. The Journal of General Physiology. ISSN 0022-1295. 124, p. 173–184. Full text in Research Archive
• Haug, Trude M; Hafting, Torkel & Sand, Olav (2004). Inhibition of BK channels contributes to the second phase of the response to TRH in clonal rat anterior pituitary cells. Acta Physiologica Scandinavica. ISSN 0001-6772. 180, p. 347–357. Full text in Research Archive
• Haug, Trude M (2004). Regulation of K+ flow by a ring of negative charges in the outer pore of the BKCa channels. Part II: Ionic and gating currents. The Journal of General Physiology. ISSN 0022-1295. 124, p. 185–197. Full text in Research Archive
• Haug, Trude M & Storm, Johan Fredrik (2000). Protein kinase A mediates the modulation of the slow Ca2+-dependent K+ current, IsAHP, by the neuropeptides CRF, VIP and CGRP in hippocampal pyramidal neurons. Journal of Neurophysiology. ISSN 0022-3077. 83, p. 2071–2079. Full text in Research Archive
• Pedarzani, P.; Haug, Trude M; Storm, Johan Fredrik & Stühmer, W. (1998). Modulation of the slow Ca2+-activated K+ current sIAHP by a phosphatase/kinase balance under basal conditions in rat CA1 pyramidal neurons. Journal of Neurophysiology. ISSN 0022-3077. 79(6), p. 3252–3256. Full text in Research Archive
• Haug, Trude M (1998). Molecular determinants of KATP channel inhibition by ATP. EMBO Journal. ISSN 0261-4189. 17, p. 3290–3296. Full text in Research Archive
• Gribble, Fiona M; Tucker, SJ; Haug, Trude M & Ashcroft, Fran M (1998). MgATP activates the beta cell KATP channel by interaction with its SUR1 subunit. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 95, p. 7185–7190. Full text in Research Archive
• Haug, Trude M & Sand, Olav (1997). BK channels in intact clonal rat pituitary cells are activated by physiological elevations of the cytosolic Ca2+ concentration at the normal resting potential. Acta Physiologica Scandinavica. ISSN 0001-6772. 161, p. 227–237. Full text in Research Archive

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• Halnes, Geir; Tennøe, Simen; Einevoll, Gaute; Haug, Trude; Weltzien, Finn-Arne & Hodne, Kjetil (2019). A computational model of the spontaneous activity of gonadotrophin-releasing cells in the teleost fish models. Full text in Research Archive
• Mobråten, Kaia; Haug, Trude M; Kleiveland, Charlotte Ramstad & Lea, Tor Erling (2013). Omega-3 and omega-6 PUFAs both activated GPR120 in Caco2 cells. Full text in Research Archive
• Sand, Sverre L.; Nissen-Meyer, Jon; Sand, Olav & Haug, Trude M (2011). The cationic peptide plantaricin A produced by Lactobacillus plantarum permeabilizes eukaryotic cell membranes by a mechanism dependent on negative surface charge linked to glycosylated membrane proteins. Acta Physiologica. ISSN 1748-1708. 202, p. P56–P56. Full text in Research Archive
• Haug, Trude M; Sand, Sverre L.; Phung, Danh; Hardy, Simpn P. & Sand, Olav (2009). The Bacillus cereus Nhe enterotoxin forms gigantic channels in cell membranes. Acta Physiologica. ISSN 1748-1708. 196, p. P30–P30. Full text in Research Archive Show summary

  The Nhe enterotoxin was discovered following a large food-poisoning outbreak in Norway in 1995, and consists of three separate proteins: Nhe-A, -B, and -C. The Nhe complex induces cell lysis in clonal epithelial cell lines (Vero and Caco2), and forms channels of 200-700 pS conductance in planar lipid bilayers (Fagerlund et al. 2008). Electrophysiological effects of Nhe on cell membranes have previously not been examined. We have studied the membrane effects of Nhe on Vero cells and clonal pituitary cells (GH4 cells) by patch clamp recordings and microfluorometric (fura-2) monitoring of the cytosolic Ca2+ level ([Ca2+]i ) and fluorochrome concentration. Cell lysis was assessed by measuring the release of lactate dehydrogenase (LDH). Within 30 min, preparations of Nhe from 5 hr culture supernatants of B. cereus NVH75/95 induced massive LDH release, i.e., 90-100 % of maximum (triton X-100) in both cell types. Whole-cell voltage clamp recordings revealed Nhe-induced insertion of gigantic channels after a delay of 1-3 min. The mean single channel conductance was estimated to 8 nS, which is more than 10 times the mean channel conductance in planar lipid bilayers. The reversal potential of the channel currents was close to 0 mV, indicating an unselective channel. To our knowledge, this is the highest channel conductance reported in cell membranes under quasi-physiological conditions. Nhe also increased [Ca2+]i abruptly to saturating levels after a similar delay, followed by a gradual loss of fluorochrome from the cytosol. We conclude that the Nhe toxin complex induces cell lysis by forming large conductance channels in the plasma membrane of target epithelia. Reference: Fagerlund A., Lindbäck T., Storset A.K., Granum P.E. and Hardy S.P. 2008. Microbiology 154, 693-704.

• Andersland, Kristin; Johansen, Guro Five; Haug, Trude M & Sand, Olav (2008). THE ANTIMICROBIAL PEPTIDE PLANTARICIN A PERMEABILIZES LIVER AND KIDNEY CELLS. Acta Physiologica. ISSN 1748-1708. 193, p. P17–P17. Full text in Research Archive
• Haug, Trude M; Hodne, Kjetil; Weltzien, Finn-Arne & Sand, Olav (2007). Signaling properties of teleost gonadotropes with a first study from atlantic cod. Acta Physiologica. ISSN 1748-1708. 190, p. 504–504. Full text in Research Archive
• Kristiansen, Per Eugen; Sand, Sverre; Haug, Trude M; Sand, Olav; Fimland, Gunnar & Zhao, Hongxia [Show all 10 contributors for this article] (2006). Structure and Mode of Action of the Membrane-Permeabilizing Antimicrobial Peptide Pheromone Plantaricin A. Full text in Research Archive
• Haug, Trude M; Hodne, Kjetil; Weltzien, Finn-Arne & Sand, Olav (2006). Electrophysiological properties of pituitary cells in primary cultures from atlantic cod (Gadus morhua). Acta Physiologica. ISSN 1748-1708. 187, p. P23–P23. Full text in Research Archive
• Sand, Sverre Larsstuvold; Haug, Trude M; Fimland, Gunnar; Nissen-Meyer, Jon & Sand, Olav (2006). Membrane-permeabilizing effects of the bacterial peptide Plantaricin A on rat anterior pituitary cells. Acta Physiologica. ISSN 1748-1708. 187, p. P11–P11. Full text in Research Archive
• Sand, Sverre L.; Haug, Trude M; Nissen-Meyer, Jon & Sand, Olav (2006). Clonal rat anterior pituitary cells (GH4 cells) are permeabilized by plantaricin A, a peptide pheromone produced by Lactobacillus plantarum. SFN Abstract Viewer/Itinerary Planner. Full text in Research Archive Show summary

  Antimicrobial peptides and proteins, generally referred to as bacteriocins, are produced by numerous strains of bacteria. Plantaricin A (PlnA) is a 26-mer peptide pheromone that induces bacteriocin production in the strain from which it is released, Lactobacillus plantarum C11. Although pheromone activity is the prime biological function of PlnA, the peptide also has membrane-permeabilizing strain-specific antibacterial activity. The pheromone activity of PlnA depends on its binding to specific receptors, preceded by a non-chiral interaction with the target cell membrane. The latter mechanism is presumably responsible for the membrane-permeabilizing effect on sensitive strains. We have studied the effect of PlnA on the GH4 cell line using the patch clamp techniques. This neoplastic cell line is derived from a rat anterior pituitary tumor, and is commonly used as a model system for anterior pituitary cells. Whole-cell current clamp recordings revealed massive membrane permeabilization within 5 s after exposure to 10-100 µM PlnA. The membrane depolarized to abut 0 mV and the membrane resistance decreased to a mere fraction of the initial value after less than 1 min. Recordings from outside-out patches during exposure to 10 µM PlnA showed that the induced membrane current reversed at 0 mV, indicating an unspecific conductance increase. The D-form of the peptide, composed of only D-amino acids, was as effective as the L-form, indicating that PlnA exerts its membrane-permeabilizing effect through a non-chiral mechanism. Recordings from inside-out patches during exposure of the internal leaflet of the cell membrane to 1 mM PlnA showed both unaltered membrane conductance and BK channel activity. These results suggest that the peptide does not interfere with the membrane integrity when the inner leaflet is exposed. Surprisingly, the normal counterparts of the GH4 cell line, primary cell cultures of rat anterior pituitary, were insensitive to the peptide. Even at a concentration of 1 mM, PlnA had no detectable effects on the membrane conductance of normal anterior pituitary cells in any of the patch clamp configurations. Thus, the peptide seems to differentiate not only between membrane leaflets, but also between plasma membranes. This characteristic makes the membrane permeabilizing effects of PlnA particularly intriguing.

• Sand, Olav; Haug, Trude M & Mørk, Halvor (2005). Electrophysiological properties of anterior pituitary cells. Acta Physiologica Scandinavica. ISSN 0001-6772. 183, p. A402–A402. Full text in Research Archive
• Haug, Trude M; Hafting, Torkel & Sand, Olav (2004). Contribution of BK channels to the resting conductance and the second phase of the response to TRH in anterior pituitary cells (GH4C1cells). Acta Physiologica Scandinavica. ISSN 0001-6772. 181, p. A140–A140. Full text in Research Archive
• Mørk, Halvor; Haug, Trude M & Sand, Olav (2004). Contribution of different Ca2+-activated K+-channels to the first phase of the TRH response in clonal anterior pituitary cells (GH4 cells). Acta Physiologica Scandinavica. ISSN 0001-6772. 181, p. A140–A140. Full text in Research Archive
• Haug, Trude M; Hafting-Fyhn, Torkel & Sand, Olav (2003). Contribution of BK channels to the second phase of the response to TRH in anterior pituitary cells (GH4 cells). SFN Abstract Viewer/Itinerary Planner. Full text in Research Archive
• Haug, Trude M; Ciani, Sergio; Toro, Ligia; Stefani, Enrico & Olcese, Riccardo (2003). Neutralization of the aspartate in the GYGD pore sequence affects gating properties in BKCa channels. Full text in Research Archive
• Haug, Trude M; Olcese, Riccardo; Ciani, Sergio; Toro, Ligia & Stefani, Enrico (2002). Regulation of inward potassium flow by a negative residue in the outer vestibule of the MaxiK channel pore. Full text in Research Archive
• Stefani, Enrico; Haug, Trude M; Ciani, Sergio; Toro, Ligia & Olcese, Riccardo (2002). Conduction of K ions through BKCa channels is enhanced by a negatively charged residue near the pore (D292). Full text in Research Archive
• Olcese, Riccardo; Zhu, Ning; Haug, Trude M; Toro, Ligia & Stefani, Enrico (2002). Conformational changes in BK(Ca) channel during channel opening and closing revealed by optical methods. Full text in Research Archive
• Olcese, Riccardo; Zhu, Ning; Haug, Trude M; Toro, Ligia & Stefani, Enrico (2001). Voltage dependent conformational changes in MaxiK channels assessed by fluorescent labeling. Full text in Research Archive
• Haug, Trude M; Olcese, Riccardo; Zhu, Ning; Toro, Ligia & Stefani, Enrico (2001). Reduced Ca2+-sensitivity in the D292N mutant of hSlo potassium channel pore. Full text in Research Archive
• Storm, Johan Fredrik; Pedarzani, P. & Haug, Trude M (2000). Modulation of K+ channels in hippocampal neurons: transmitters acting via cyclic AMP enhance the excitability through kinase-dependent and -independent modulation of AHP- and h-channels. Full text in Research Archive
• Haug, Trude M & Storm, Johan Fredrik (1998). Peptidergic modulation via protein kinase A of the slow Ca2+-dependent K+ current IAHP in hippocampal pyramidal cells. Full text in Research Archive
• Haug, Trude M & Sand, Olav (1997). BK-channels in cell-attached patches of clonal pituitary cells (GH4 cells). Abstracts - Society for Neuroscience. ISSN 0190-5295. 23(2), p. 1481–1481. Full text in Research Archive
• Haug, Trude M & Sand, Olav (1996). Activation of BK-channels in intact clonal pituitary cells. Acta Physiologica Scandinavica. ISSN 0001-6772. 157, p. 51A–51A. Full text in Research Archive
• Haug, Trude M & Storm, Johan Frederik (1999). Ca2+ -activated and ATP-sensitive potassium channels in endocrine cells and neurons. Universitetet i Oslo. Full text in Research Archive

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