Kjetil Wessel Andressen

• Andressen, Kjetil Wessel; Sedneva-Lugovets, Daiana; Ovesen, Mette; Calejo, Ana Isabel Costa; Arunthavarajah, Dulasi & Levy, Finn Olav (2025). Regulation, effects and monitoring of compartmented cGMP signalling in cardiomyocytes—current status. British Journal of Pharmacology. ISSN 0007-1188. doi: 10.1111/bph.70144. Full text in Research Archive Show summary

  Cyclic guanosine 3′,5′‐monophosphate (cGMP) signalling in cardiomyocytes is intricately organized within cellular compartments, influencing several physiological and pathophysiological processes in the heart. We review how compartmented cGMP signalling is regulated and can be monitored within cardiomyocytes, emphasizing recent advances and methodologies. Three different guanylyl cyclases (GCs), two particulate (GC‐A and GC‐B) and one soluble (sGC), produce distinct cGMP pools, giving rise to differential signalling in cardiomyocytes. Phosphodiesterases (PDEs) maintain intracellular cGMP gradients. The use of intracellular biosensors, particularly those based on fluorescence resonance energy transfer (FRET), has enabled visualization of cGMP dynamics with high spatial and temporal resolution. These tools, which are constantly being improved, allow the observation of localized cGMP signals and have revealed discrete signalling compartments regulated by the subcellular localization of GCs and PDEs. Understanding these complex signalling networks in cardiomyocytes of healthy and diseased hearts can guide potential therapeutic approaches to treat cardiac dysfunction, including hypertrophy and heart failure. In conclusion, new tools are refining our understanding of compartmented cGMP signalling, which may lead to novel strategies for targeted therapeutic interventions in cardiovascular diseases.

• Thulin, Malin Hagberg; Ramberg, Håkon; Nielsen, Heidi Kristin; Grytli, Helene Hartvedt; Sivanesan, Shivanthe & Pandya, Abhilash D. [Show all 15 contributors for this article] (2025). Beta-blockers prolong response to androgen deprivation therapy in prostate cancer through modulation of the neuro-immuno-oncology axis. Journal of Translational Medicine. 23(1). doi: 10.1186/s12967-025-06644-7. Full text in Research Archive Show summary

  Background The therapeutic impact of beta-blockers (BB), beta-adrenergic receptor antagonists, on prostate cancer remains controversial. The underlying health conditions of BB users complicate the ability to isolate and evaluate the specific effects of these drugs on the tumour cells. This study investigated whether BBs, by inhibiting sympathetic nerve signalling, extended the duration of androgen deprivation therapy (ADT) effectiveness in patients with de novo metastatic hormone sensitive prostate cancer and in prostate cancer xenograft models, while also uncovering the molecular mechanisms involved. Methods An analysis was conducted on prospectively collected data from the Cancer Registry of Norway, Norwegian Prescription Database, and Norwegian Cause of Death Registry focusing on patients with de novo metastatic prostate cancer undergoing ADT using the commencement of second-line treatment as the endpoint. In addition, the causal effect of BB treatment was studied in two different hormone-sensitive prostate cancer xenograft mouse models. Prior to treatment, mice were surgically castrated, to mimic ADT, and tumour progression was tracked by measuring serum PSA levels. RNA sequencing was performed on xenografted orthotopic tumours to investigate the underlying mechanisms, utilizing annotation based on human data and protein levels were validated by the Protein Simple Immunoassay. Immune-related effects were evaluated using immunohistochemistry on tumour tissue and measuring neopterin levels, along with 92 analytes, using the OLINK proximity extension assay on serum samples from xenografted mice and prostate cancer patients, both BB users and non-users. Results A competitive risk analysis indicated that BB treatment postponed the initiation of second-line treatment in prostate cancer patients on ADT. Additionally, in both prostate cancer xenograft models, BB treatment reduced tumour burden and delayed progression to castration-resistant prostate cancer. Mechanistically, BB treatment suppressed androgen receptor signalling and induced a metabolic shift by up-regulating oxidative phosphorylation transcripts and down-regulating those involved in fatty acid synthesis and the PI3K/AKT/mTOR pathway. Additionally, BB treatment increased serum pro-inflammatory cytokines, such as the IL23/IL17 axis, in both xenografted mice and in patient samples. Enhanced intra-tumoral CD68+ immune cell infiltration was also observed in the tumours. Conclusion The data suggest that BB combined with ADT delay the progression to castration-resistant prostate cancer. This may be achieved by influencing androgen receptor activity, adjusting energy metabolism and fostering a pro-inflammatory antitumoral microenvironment

• Osnes, Jan-Bjørn; Andressen, Kjetil Wessel & Levy, Finn Olav (2024). Statiner: 50-årsjubilant med nye overraskelser på lur. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 144(8). doi: 10.4045/tidsskr.24.0165. Full text in Research Archive
• Calamera, Gaia; Moltzau, Lise Roman; Levy, Finn Olav & Andressen, Kjetil Wessel (2022). Phosphodiesterases and Compartmentation of cAMP and cGMP Signaling in Regulation of Cardiac Contractility in Normal and Failing Hearts. International Journal of Molecular Sciences. ISSN 1661-6596. 23:2145(4), p. 1–24. doi: 10.3390/ijms23042145. Full text in Research Archive Show summary

  Cardiac contractility is regulated by several neural, hormonal, paracrine, and autocrine factors. Amongst these, signaling through β-adrenergic and serotonin receptors generates the second messenger cyclic AMP (cAMP), whereas activation of natriuretic peptide receptors and soluble guanylyl cyclases generates cyclic GMP (cGMP). Both cyclic nucleotides regulate cardiac contractility through several mechanisms. Phosphodiesterases (PDEs) are enzymes that degrade cAMP and cGMP and therefore determine the dynamics of their downstream effects. In addition, the intracellular localization of the different PDEs may contribute to regulation of compartmented signaling of cAMP and cGMP. In this review, we will focus on the role of PDEs in regulating contractility and evaluate changes in heart failure.

• Manfra, Ornella; Calamera, Gaia; Froese, Alexander; Arunthavarajah, Dulasi; Surdo, Nicoletta C. & Meier, Silja [Show all 14 contributors for this article] (2022). CNP regulates cardiac contractility and increases cGMP near both SERCA and TnI: difference from BNP visualized by targeted cGMP biosensors. Cardiovascular Research (CVR). ISSN 0008-6363. 118(6), p. 1506–1519. doi: 10.1093/cvr/cvab167. Full text in Research Archive Show summary

  Abstract Aims Guanylyl cyclase-B (GC-B; natriuretic peptide receptor-B, NPR-B) stimulation by C-type natriuretic peptide (CNP) increases cGMP and causes a lusitropic and negative inotropic response in adult myocardium. These effects are not mimicked by NPR-A (GC-A) stimulation by brain natriuretic peptide (BNP), despite similar cGMP increase. More refined methods are needed to better understand the mechanisms of the differential cGMP signalling and compartmentation. The aim of this work was to measure cGMP near proteins involved in regulating contractility to understand compartmentation of cGMP signalling in adult cardiomyocytes. Methods and results We constructed several fluorescence resonance energy transfer (FRET)-based biosensors for cGMP subcellularly targeted to phospholamban (PLB) and troponin I (TnI). CNP stimulation of adult rat cardiomyocytes increased cGMP near PLB and TnI, whereas BNP stimulation increased cGMP near PLB, but not TnI. The phosphodiesterases PDE2 and PDE3 constrained cGMP in both compartments. Local receptor stimulation aided by scanning ion conductance microscopy (SICM) combined with FRET revealed that CNP stimulation both in the t-tubules and on the cell crest increases cGMP similarly near both TnI and PLB. In ventricular strips, CNP stimulation, but not BNP, induced a lusitropic response, enhanced by inhibition of either PDE2 or PDE3, and a negative inotropic response. In cardiomyocytes from heart failure rats, CNP increased cGMP near PLB and TnI more pronounced than in cells from sham-operated animals. Conclusion These targeted biosensors demonstrate that CNP, but not BNP, increases cGMP near TnI in addition to PLB, explaining how CNP, but not BNP, is able to induce lusitropic and negative inotropic responses.

• Faleeva, Maria; Diakonov, Ivan; Srivastava, Prashant; Ramuz, Masoud; Calamera, Gaia & Andressen, Kjetil Wessel [Show all 12 contributors for this article] (2022). Compartmentation of cGMP Signaling in Induced Pluripotent Stem Cell Derived Cardiomyocytes during Prolonged Culture. Cells. 11:3257(20), p. 1–17. doi: 10.3390/cells11203257. Full text in Research Archive Show summary

  The therapeutic benefit of stimulating the cGMP pathway as a form of treatment to combat heart failure, as well as other fibrotic pathologies, has become well established. However, the development and signal compartmentation of this crucial pathway has so far been overlooked. We studied how the three main cGMP pathways, namely, nitric oxide (NO)-cGMP, natriuretic peptide (NP)-cGMP, and β3-adrenoreceptor (AR)-cGMP, mature over time in culture during cardiomyocyte differentiation from human pluripotent stem cells (hPSC-CMs). After introducing a cGMP sensor for Förster Resonance Energy Transfer (FRET) microscopy, we used selective phosphodiesterase (PDE) inhibition to reveal cGMP signal compartmentation in hPSC-CMs at various times of culture. Methyl-β-cyclodextrin was employed to remove cholesterol and thus to destroy caveolae in these cells, where physical cGMP signaling compartmentalization is known to occur in adult cardiomyocytes. We identified PDE3 as regulator of both the NO-cGMP and NP-cGMP pathway in the early stages of culture. At the late stage, the role of the NO-cGMP pathway diminished, and it was predominantly regulated by PDE1, PDE2, and PDE5. The NP-cGMP pathway shows unrestricted locally and unregulated cGMP signaling. Lastly, we observed that maturation of the β3-AR-cGMP pathway in prolonged cultures of hPSC-CMs depends on the accumulation of caveolae. Overall, this study highlighted the importance of structural development for the necessary compartmentation of the cGMP pathway in maturing hPSC-CMs.

• Danielsen, Tore Kristian; Sadredini, Mani; Manotheepan, Ravinea; Aronsen, Jan Magnus; Frisk, Michael & Haugsten, Marie Hansen [Show all 13 contributors for this article] (2021). Exercise training stabilizes RyR2-dependent Ca2+ release in post-infarction heart failure. Frontiers in Cardiovascular Medicine. 7. doi: 10.3389/fcvm.2020.623922. Full text in Research Archive Show summary

  Aim: Dysfunction of the cardiac ryanodine receptor (RyR2) is an almost ubiquitous finding in animal models of heart failure (HF) and results in abnormal Ca 2+ release in cardiomyocytes that contributes to contractile impairment and arrhythmias. We tested whether exercise training (ET), as recommended by current guidelines, had the potential to stabilize RyR2-dependent Ca 2+ release in rats with post-myocardial infarction HF. Materials and Methods: We subjected male Wistar rats to left coronary artery ligation or sham operations. After 1 week, animals were characterized by echocardiography and randomized to high-intensity interval ET on treadmills or to sedentary behavior (SED). Running speed was adjusted based on a weekly VO 2max test. We repeated echocardiography after 5 weeks of ET and harvested left ventricular cardiomyocytes for analysis of RyR2-dependent systolic and spontaneous Ca 2+ release. Phosphoproteins were analyzed by Western blotting, and beta-adrenoceptor density was quantified by radioligand binding. Results: ET increased VO 2max in HF-ET rats to 127% of HF-SED ( P < 0.05). This coincided with attenuated spontaneous SR Ca 2+ release in left ventricular cardiomyocytes from HF-ET but also reduced Ca 2+ transient amplitude and slowed Ca 2+ reuptake during adrenoceptor activation. However, ventricular diameter and fractional shortening were unaffected by ET. Analysis of Ca 2+ homeostasis and major proteins involved in the regulation of SR Ca 2+ release and reuptake could not explain the attenuated spontaneous SR Ca 2+ release or reduced Ca 2+ transient amplitude. Importantly, measurements of beta-adrenoceptors showed a normalization of beta 1 -adrenoceptor density and beta 1 :beta 2 -adrenoceptor ratio in HF-ET. Conclusion: ET increased aerobic capacity in post-myocardial infarction HF rats and stabilized RyR2-dependent Ca 2+ release. Our data show that these effects of ET can be gained without major alterations in SR Ca 2+ regulatory proteins and indicate that future studies should include upstream parts of the sympathetic signaling pathway.

• Jang, Wonjo; Adams, C. Elizabeth; Liu, Heng; Zhang, Cheng; Levy, Finn Olav & Andressen, Kjetil Wessel [Show all 7 contributors for this article] (2020). An inactive receptor-G protein complex maintains the dynamic range of agonist-induced signaling. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 117(48), p. 30755–30762. doi: 10.1073/pnas.2010801117. Full text in Research Archive Show summary

  Agonist binding promotes activation of G protein-coupled receptors (GPCRs) and association of active receptors with G protein heterotrimers. The resulting active-state ternary complex is the basis for conventional stimulus-response coupling. Although GPCRs can also associate with G proteins before agonist binding, the impact of such preassociated complexes on agonist-induced signaling is poorly understood. Here we show that preassociation of 5-HT 7 serotonin receptors with G s heterotrimers is necessary for agonist-induced signaling. 5-HT 7 receptors in their inactive state associate with G s , as these complexes are stabilized by inverse agonists and receptor mutations that favor the inactive state. Inactive-state 5-HT 7 –G s complexes dissociate in response to agonists, allowing the formation of conventional agonist–5-HT 7 –G s ternary complexes and subsequent G s activation. Inactive-state 5-HT 7 –G s complexes are required for the full dynamic range of agonist-induced signaling, as 5-HT 7 receptors spontaneously activate G s variants that cannot form inactive-state complexes. Therefore, agonist-induced signaling in this system involves two distinct receptor-G protein complexes, a conventional ternary complex that activates G proteins and an inverse-coupled binary complex that maintains the inactive state when agonist is not present.

• Calamera, Gaia; Li, Dan; Ulsund, Andrea Hembre; Kim, Jeong Joo; Neely, Oliver C. & Moltzau, Lise Roman [Show all 11 contributors for this article] (2019). FRET-based cyclic GMP biosensors measure low cGMP concentrations in cardiomyocytes and neurons. Communications Biology. 2:394, p. 1–12. doi: 10.1038/s42003-019-0641-x. Full text in Research Archive Show summary

  Several FRET (fluorescence resonance energy transfer)-based biosensors for intracellular detection of cyclic nucleotides have been designed in the past decade. However, few such biosensors are available for cGMP, and even fewer that detect low nanomolar cGMP concentrations. Our aim was to develop a FRET-based cGMP biosensor with high affinity for cGMP as a tool for intracellular signaling studies. We used the carboxyl-terminal cyclic nucleotide binding domain of Plasmodium falciparum cGMP-dependent protein kinase (PKG) flanked by different FRET pairs to generate two cGMP biosensors (Yellow PfPKG and Red PfPKG). Here, we report that these cGMP biosensors display high affinity for cGMP (EC50 of 23 ± 3 nM) and detect cGMP produced through soluble guanylyl cyclase and guanylyl cyclase A in stellate ganglion neurons and guanylyl cyclase B in cardiomyocytes. These biosensors are therefore optimal tools for real-time measurements of low concentrations of cGMP in living cells.

• Ulsund, Amanda Hembre; Dahl, Marie; Frimurer, Thomas; Manfra, Ornella; Schwartz, Thue W. & Levy, Finn Olav [Show all 7 contributors for this article] (2018). Preassociation between the 5-HT7 serotonin receptor and G protein Gs: molecular determinants and association with low potency activation of adenylyl cyclase. The FASEB Journal. ISSN 0892-6638. 33(3), p. 3870–3886. doi: 10.1096/fj.201800805RR. Full text in Research Archive
• Moltzau, Lise Roman; Meier, Silja; Andressen, Kjetil Wessel & Levy, Finn Olav (2017). Compartmentation of Natriuretic Peptide Signalling in Cardiac Myocytes: Effects on Cardiac Contractility and Hypertrophy. In Nikolaev, Viacheslav & Zaccolo, Manuela (Ed.), Microdomains in the Cardiovascular System.. Springer. ISSN 9783319545783. p. 245–271. doi: 10.1007/978-3-319-54579-0_12. Full text in Research Archive
• Meier, Silja; Andressen, Kjetil Wessel; Aronsen, Jan Magnus; Sjaastad, Ivar; Hougen, Karina & Skomedal, Tor [Show all 10 contributors for this article] (2017). PDE3 inhibition by C-type natriuretic peptide-induced cGMP enhances cAMP-mediated signaling in both non-failing and failing hearts. European Journal of Pharmacology. ISSN 0014-2999. 812, p. 174–183. doi: 10.1016/j.ejphar.2017.07.014. Full text in Research Archive
• Andressen, Kjetil Wessel; Ulsund, Andrea Hembre; Krobert, Kurt Allen; Lohse, Martin J.; Bünemann, Moritz & Levy, Finn Olav (2017). Related GPCRs couple differently to Gs: preassociation between G protein and 5-HT7 serotonin receptor reveals movement of Gαs upon receptor activation. The FASEB Journal. ISSN 0892-6638. 32(2), p. 1059–1069. doi: 10.1096/fj.201700486R. Full text in Research Archive
• Olberg, Dag Erlend; Bauer, Nadine; Andressen, Kjetil Wessel; Hjornevik, Trine; Cumming, Paul & Levy, Finn Olav [Show all 9 contributors for this article] (2016). Brain penetrant small molecule 18F-GnRH receptor (GnRH-R) antagonists: Synthesis and preliminary positron emission tomography imaging in rats. Nuclear Medicine and Biology. ISSN 0969-8051. 43(8), p. 478–489. doi: 10.1016/j.nucmedbio.2016.05.003. Full text in Research Archive
• Ørstavik, Øivind; Manfra, Ornella; Andressen, Kjetil Wessel; Andersen, Geir Øystein; Skomedal, Tor & Osnes, Jan-Bjørn [Show all 8 contributors for this article] (2015). The inotropic effect of the active metabolite of levosimendan, OR-1896, is mediated through inhibition of PDE3 in rat ventricular myocardium. PLOS ONE. 10(3). doi: 10.1371/journal.pone.0115547. Full text in Research Archive Show summary

  Aims We recently published that the positive inotropic response (PIR) to levosimendan can be fully accounted for by phosphodiesterase (PDE) inhibition in both failing human heart and normal rat heart. To determine if the PIR of the active metabolite OR-1896, an important mediator of the long-term clinical effects of levosimendan, also results from PDE3 inhibition, we compared the effects of OR-1896, a representative Ca2+ sensitizer EMD57033 (EMD), levosimendan and other PDE inhibitors. Methods Contractile force was measured in rat ventricular strips. PDE assay was conducted on rat ventricular homogenate. cAMP was measured using RII_epac FRET-based sensors. Results OR-1896 evoked a maximum PIR of 33±10% above basal at 1 μM. This response was amplified in the presence of the PDE4 inhibitor rolipram (89±14%) and absent in the presence of the PDE3 inhibitors cilostamide (0.5±5.3%) or milrinone (3.2±4.4%). The PIR was accompanied by a lusitropic response, and both were reversed by muscarinic receptor stimulation with carbachol and absent in the presence of β-AR blockade with timolol. OR-1896 inhibited PDE activity and increased cAMP levels at concentrations giving PIRs. OR-1896 did not sensitize the concentration-response relationship to extracellular Ca2+. Levosimendan, OR-1896 and EMD all increased the sensitivity to β-AR stimulation. The combination of either EMD and levosimendan or EMD and OR-1896 further sensitized the response, indicating at least two different mechanisms responsible for the sensitization. Only EMD sensitized the α1-AR response. Conclusion The observed PIR to OR-1896 in rat ventricular strips is mediated through PDE3 inhibition, enhancing cAMP-mediated effects. These results further reinforce our previous finding that Ca2+ sensitization does not play a significant role in the inotropic (and lusitropic) effect of levosimendan, nor of its main metabolite OR-1896.

• Manfra, Ornella; Craenenbroeck, Kathleen Van; Skieterska, Kamila; Frimurer, Thomas; Schwartz, Thue W. & Levy, Finn Olav [Show all 7 contributors for this article] (2015). Downregulation of 5-HT7 Serotonin Receptors by the Atypical Antipsychotics Clozapine and Olanzapine. Role of Motifs in the C-Terminal Domain and Interaction with GASP-1. ACS Chemical Neuroscience. 6(7), p. 1206–1218. doi: 10.1021/cn500339p. Full text in Research Archive
• Olberg, Dag Erlend; Hausner, Sven H.; Bauer, Nadine; Klaveness, Jo; Indrevoll, Bård & Andressen, Kjetil Wessel [Show all 10 contributors for this article] (2015). Radiosynthesis of high affinity fluorine-18 labeled GnRH peptide analogues: in vitro studies and in vivo assessment of brain uptake in rats. MedChemComm. ISSN 2040-2503. 6, p. 708–714. doi: 10.1039/c4md00486h. Full text in Research Archive
• Impellizzeri, Agata Antonina Rita; Pappalardo, Matteo; Basile, Livia; Manfra, Ornella; Andressen, Kjetil Wessel & Krobert, Kurt Allen [Show all 9 contributors for this article] (2015). Identification of essential residues for binding and activation in the human 5-HT7(a) serotonin receptor by molecular modeling and site-directed mutagenesis. Frontiers in Behavioral Neuroscience. 9(MAY). doi: 10.3389/fnbeh.2015.00092. Full text in Research Archive Show summary

  The human 5-HT7 receptor is expressed in both the central nervous system and peripheral tissues and is a potential drug target in behavioral and psychiatric disorders. We examined molecular determinants of ligand binding and G protein activation by the human 5-HT7(a) receptor. The role of several key residues in the 7th transmembrane domain (TMD) and helix 8 were elucidated combining in silico and experimental mutagenesis. Several single and two double point mutations of the 5-HT7(a) wild type receptor were made (W7.33V, E7.35T, E7.35R, E7.35D, E7.35A, R7.36V, Y7.43A, Y7.43F, Y7.43T, R8.52D, D8.53K; E7.35T-R7.36V, R8.52D-D8.53K), and their effects upon ligand binding were assessed by radioligand binding using a potent agonist (5-CT) and a potent antagonist (SB269970). In addition, the ability of the mutated 5-HT7(a) receptors to activate G protein after 5-HT-stimulation was determined through activation of adenylyl cyclase. In silico investigation on mutated receptors substantiated the predicted importance of TM7 and showed critical roles of residues E7.35, W7.33, R7.36 and Y7.43 in agonist and antagonist binding and conformational changes of receptor structure affecting adenylyl cyclase activation. Experimental data showed that mutants E7.35T and E7.35R were incapable of ligand binding and adenylyl cyclase activation, consistent with a requirement for a negatively charged residue at this position. The mutant R8.52D was unable to activate adenylyl cyclase, despite unaffected ligand binding, consistent with the R8.52 residue playing an important role in the receptor-G protein interface. The mutants Y7.43A and Y7.43T displayed reduced agonist binding and AC agonist potency, not seen in Y7.43F, consistent with a requirement for an aromatic residue at this position. Knowledge of the molecular interactions important in h5-HT7 receptor ligand binding and G protein activation will aid the design of selective h5-HT7 receptor ligands for potential pharmacological use.

• Andressen, Kjetil Wessel; Manfra, Ornella; Brevik, Christian Hellesylt; Ulsund, Andrea Hembre; Vanhoenacker, Peter & Levy, Finn Olav [Show all 7 contributors for this article] (2015). The atypical antipsychotics clozapine and olanzapine promote down-regulation and display functional selectivity at human 5-HT7 receptors. British Journal of Pharmacology. ISSN 0007-1188. 172(15), p. 3846–3860. doi: 10.1111/bph.13169. Full text in Research Archive
• Olberg, Dag Erlend; Andressen, Kjetil Wessel; Levy, Finn Olav; Klaveness, Jo; Haraldsen, Ira Hebold & Sutcliffe, Julie L. (2014). Synthesis and in vitro evaluation of small-molecule [18F] labeled gonadotropin-releasing hormone (GnRH) receptor antagonists as potential PET imaging agents for GnRH receptor expression. Bioorganic & Medicinal Chemistry Letters. ISSN 0960-894X. 24(7), p. 1846–1850. doi: 10.1016/j.bmcl.2014.02.002. Full text in Research Archive
• Brudeli, Bjarne; Navaratnarajah, Mirusha; Andressen, Kjetil Wessel; Manfra, Ornella; Moltzau, Lise Roman & Nilsen, Nils Olav [Show all 8 contributors for this article] (2014). Discovery and pharmacological profile of new hydrophilic 5-HT4 receptor antagonists. Bioorganic & Medicinal Chemistry Letters. ISSN 0960-894X. 24(18), p. 4598–4602. doi: 10.1016/j.bmcl.2014.06.083. Full text in Research Archive
• Kilander, Michael Brita Christina; Petersen, Julian; Andressen, Kjetil Wessel; Ganji, Ranjani Sri; Levy, Finn Olav & Schuster, Jens [Show all 9 contributors for this article] (2014). Disheveled regulates precoupling of heterotrimeric G proteins to Frizzled 6. The FASEB Journal. ISSN 0892-6638. 28(5), p. 2293–2305. doi: 10.1096/fj.13-246363. Full text in Research Archive
• Brudeli, Bjarne; Moltzau, Lise Roman; Nguyen, Hong Cam Thi; Andressen, Kjetil Wessel; Nilsen, Nils Olav & Levy, Finn Olav [Show all 7 contributors for this article] (2013). Synthesis and pharmacological properties of a new hydrophilic and orally bioavailable 5-HT4 antagonist. European Journal of Medicinal Chemistry. ISSN 0223-5234. 64, p. 629–637. doi: 10.1016/j.ejmech.2013.03.060. Full text in Research Archive
• Gellynck, Evelien; Heyninck, Karen; Andressen, Kjetil Wessel; Haegeman, Guy; Levy, Finn Olav & Vanhoenacker, Peter [Show all 7 contributors for this article] (2013). The serotonin 5-HT7 receptors: two decades of research. Experimental Brain Research. ISSN 0014-4819. 230(4), p. 555–568. doi: 10.1007/s00221-013-3694-y. Full text in Research Archive
• Brudeli, Bjarne; Andressen, Kjetil Wessel; Moltzau, Lise Roman; Nilsen, Nils Olav; Levy, Finn Olav & Klaveness, Jo (2013). Acidic biphenyl derivatives: Synthesis and biological activity of a new series of potent 5-HT4 receptor antagonists. Bioorganic & Medicinal Chemistry. ISSN 0968-0896. 21(22), p. 7134–7145. doi: 10.1016/j.bmc.2013.09.004. Full text in Research Archive
• Gellynck, Evelien; Andressen, Kjetil Wessel; Lintermans, Béatrice; Haegeman, Guy; Levy, Finn Olav & Vanhoenacker, Peter [Show all 7 contributors for this article] (2012). Biochemical and pharmacological study of N-linked glycosylation of the human serotonin 5-HT7(a) receptor. The FEBS Journal. ISSN 1742-464X. 279(11), p. 1994–2003. doi: 10.1111/j.1742-4658.2012.08581.x. Full text in Research Archive
• Brudeli, Bjarne; Moltzau, Lise Roman; Andressen, Kjetil Wessel; Krobert, Kurt Allen; Klaveness, Jo & Levy, Finn Olav (2010). Synthesis and pharmacological properties of novel hydrophilic 5-HT4 receptor antagonists. Bioorganic & Medicinal Chemistry. ISSN 0968-0896. 18(24), p. 8600–8613. doi: 10.1016/j.bmc.2010.10.011. Full text in Research Archive
• Gellynck, E; Laenen, K; Andressen, Kjetil Wessel; Lintermans, B; Martelaere, K De & Matthys, A [Show all 10 contributors for this article] (2008). Cloning, genomic organization and functionality of 5-HT7 receptor splice variants from mouse brain. Gene. ISSN 0378-1119. 426(1-2), p. 23–31. doi: 10.1016/j.gene.2008.08.011. Full text in Research Archive
• Ngai, Jacob; Iversen, Trond Methi; Andressen, Kjetil Wessel; Levy, Finn Olav; Torgersen, Knut Martin & Vang, Torkel [Show all 8 contributors for this article] (2008). The heterotrimeric G-protein α-subunit Gαq regulates TCR-mediated immune responses through an Lck-dependent pathway. European Journal of Immunology. ISSN 0014-2980. 38(11), p. 3208–3218. Full text in Research Archive
• Afzal, Faraz; Andressen, Kjetil Wessel; Mørk, Halvor Kjeang; Aronsen, Jan Magnus; Sjaastad, Ivar & Dahl, Christen Peder [Show all 10 contributors for this article] (2008). 5-HT4-elicited positive inotropic response is mediated by cAMP and regulated by PDE3 in failing rat and human cardiac ventricles. British Journal of Pharmacology. ISSN 0007-1188. 155(7), p. 1005–1014. doi: 10.1038/bjp.2008.339. Full text in Research Archive
• Vinge, Leif Erik; Andressen, Kjetil Wessel; Attramadal, Toril; Andersen, Geir Øystein; Ahmed, Muhammad Shakil & Peppel, K [Show all 12 contributors for this article] (2007). Substrate specificities of G protein-coupled receptor kinase-2 and -3 at cardiac myocyte receptors provide basis for distinct roles in regulation of myocardial function. Molecular Pharmacology. ISSN 0026-895X. 72, p. 582–591. Full text in Research Archive
• Andressen, Kjetil Wessel; Norum, Jens Henrik; Levy, Finn Olav & Krobert, Kurt Allen (2006). Activation of adenylyl cyclase by endogenous G(s)-coupled receptors in human embryonic kidney 293 cells is attenuated by 5-HT7 receptor expression. Molecular Pharmacology. ISSN 0026-895X. 69, p. 207–215. Full text in Research Archive
• Krobert, Kurt Allen; Andressen, Kjetil Wessel & Levy, Finn Olav (2006). Heterologous desensitization is evoked by both agonist and antagonist stimulation of the human 5-HT7 serotonin receptor. European Journal of Pharmacology. ISSN 0014-2999. 532, p. 1–10. Full text in Research Archive
• Qvigstad, Eirik; Brattelid, Trond; Sjaastad, Ivar; Andressen, Kjetil Wessel; Krobert, Kurt Allen & Birkeland, Jon Arne [Show all 11 contributors for this article] (2005). Appearance of a ventricular 5-HT4 receptor-mediated inotropic response to serotonin in heart failure. Cardiovascular Research (CVR). ISSN 0008-6363. 65. Full text in Research Archive Show summary

  BACKGROUND: Current pharmacological treatment of congestive heart failure (CHF) addresses changes in neurohumoral stimulation or cardiac responsiveness to such stimulation. Yet, undiscovered neurohumoral changes, adaptive or maladaptive, may occur in CHF and suggest novel pharmacological treatment. Serotonin [5-hydroxytryptamine (5-HT)] enhances contractility and causes arrhythmias through 5-HT(4) receptors in human atrium and ventricle but not through rat ventricular 5-HT(4) receptors. OBJECTIVE: We investigated whether CHF could induce ventricular responsiveness to serotonin. METHODS: Postinfarction CHF was induced in male Wistar rats by coronary artery ligation. Contractility was measured in left ventricular papillary muscles 6 weeks after infarction. Messenger RNA was quantified by RT-PCR and cAMP by RIA. RESULTS: Serotonin caused positive inotropic (-logEC(50)=7.5) and lusitropic effects in CHF but not Sham papillary muscles. The inotropic effect of 10 muM serotonin in CHF (31.3+/-2.2%) was of similar size as the effect of 10 muM isoproterenol (34.0+/-1.7%). The effects of serotonin were antagonised by GR113808 (0.5-5 nM), consistent with mediation through 5-HT(4) receptors. This was further supported by positive inotropic effects of the 5-HT(4)-selective partial agonist RS67506. Carbachol blunted the serotonin responses and serotonin increased ventricular and cardiomyocyte cAMP, consistent with coupling to G(s) and adenylyl cyclase. Quantitative RT-PCR revealed fourfold increased 5-HT(4(b)) mRNA expression in CHF vs. Sham ventricles. CONCLUSION: Functional ventricular 5-HT(4) receptors are induced by myocardial infarction and CHF of the rat heart. We propose that they are a model for ventricular 5-HT(4) receptors of human failing heart and may play a pathophysiological role in heart failure.

• Qvigstad, Eirik; Brattelid, Trond; Sjaastad, Ivar; Molenaar, P.; Birkeland, Jon Arne & Andressen, Kjetil Wessel [Show all 12 contributors for this article] (2005). Rationale for treatment of heart failure by blockade of ventricular serotonin receptors appearing in heart failure, Proceedings of the 25th European Section Meeting, International Society for Heart Research, Tromsø, Norway, June 21-25, 2005. Medimond. ISSN 9788875871642. p. 7–12. Full text in Research Archive Show summary

  Serotonin (5-hydroxytryptamine, 5-HT) enhances contractility and causes arrhythmias through human atrial 5-HT4 receptors. We recently found that porcine and human as well as failing rat cardiac ventricle also responds to serotonin through 5-HT4 receptors which, like beta-adrenoceptors, are coupled via the Gs protein to increased cAMP formation. In rats with 6-week post-infarction congestive heart failure (CHF), the maximal inotropic effect of serotonin was comparable in size with that of isoproterenol. Given the similar signalling systems utilised by the two receptors and that blockade of beta-adrenoceptors is beneficial in CHF, we propose that blockade of 5-HT4 receptors may also be beneficial in CHF.

• Brattelid, Trond; Kvingedal, Ane Marit; Krobert, Kurt Allen; Andressen, Kjetil Wessel; Bach, Trond & Hystad, Marit Elise [Show all 8 contributors for this article] (2004). Cloning, pharmacological characterisation and tissue distribution of a novel 5-HT4 receptor splice variant, 5-HT4(i). Naunyn-Schmiedeberg's Archives of Pharmacology. ISSN 0028-1298. 369(6), p. 616–628. Full text in Research Archive Show summary

  5-HT4 receptor pre-mRNA is alternatively spliced in human (h) tissue to produce several splice variants, called 5-HT4(a) to 5-HT4(h) and 5-HT4(n). Polymerase chain reaction (PCR) with primers designed to amplify both 5-HT4(a) and 5-HT4(b) amplified three additional bands in different tissues, two representing different mRNA species both encoding 5-HT4(g) and one representing mRNA for a novel splice variant named 5-HT4(i), cloned from testis and pancreas respectively. Primary and nested PCR detected both 5-HT4(g) and 5-HT4(i) in multiple tissues. Whereas 5-HT4(i), was found in all cardiovascular tissues analysed, 5-HT4(g) was mainly present in atria. However, quantitative RT-PCR indicated 5-HT4(g) expression also in cardiac ventricle. The pharmacological profiles and ability to activate adenylyl cyclase (AC) were compared between four recombinant h5-HT4 splice variants (a, b, g and i) expressed transiently and stably in HEK293 cells. Displacement of [(3)H]GR113808 with ten ligands revealed identical pharmacological profiles (affinity rank order: GR125487, SB207710, GR113808>SB203186>serotonin, cisapride, tropisetron>renzapride, 5-MeOT>5-CT). In transiently transfected HEK293 cells cisapride was a partial agonist compared to serotonin at 5-HT4(b), 5-HT4(g) and 5-HT4(i) receptors. In membranes from HEK293 cells stably expressing 5-HT4(g) (3,000 fmol/mg protein) or 5-HT4(i) (500 fmol/mg protein), serotonin and 5-MeOT were full agonists while cisapride was full agonist at 5-HT4(g) and partial agonist at 5-HT4(i), probably due to different receptor expression levels. At both 5-HT4(g) and 5-HT4(i), the behaviour of 5-HT4 receptor antagonists was dependent on receptor level. At high receptor levels, tropisetron and SB207710 and to a variable extent SB203186 and GR113808 displayed some partial agonist activity, whereas GR125487 and SB207266 reduced the AC activity below basal, indicating both receptors to be constitutively active. We conclude that the novel 5-HT4(i) receptor splice variant is pharmacologically indistinguishable from other 5-HT4 splice variants and that the 5-HT4(i) C-terminal tail does not influence coupling to AC.

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• Meier, Silja; Andressen, Kjetil Wessel; Aronsen, Jan Magnus; Sjaastad, Ivar; Skomedal, Tor & Osnes, Jan-Bjørn [Show all 9 contributors for this article] (2015). Enhancement of cAMP-mediated inotropic responses by CNP is regulated differently by PDE2 in normal and failing hearts. BMC Pharmacology and Toxicology. 16, p. A66–A66. doi: 10.1186/2050-6511-16-S1-A66. Full text in Research Archive
• Dugstad, K.; Ulsund, Andrea Hembre; Aronsen, Jan Magnus; Sjaastad, Ivar; Zaccolo, Manuela & Levy, Finn Olav [Show all 7 contributors for this article] (2014). Unraveling tight spatial regulation of 5-HT4 receptor-mediated inotropic effects using targeted FRET-based cAMP sensors. Full text in Research Archive
• Dugstad, Kari Sandanger; Andressen, Kjetil Wessel; Aronsen, Jan Magnus; Sjaastad, Ivar; Zaccolo, Manuela & Levy, Finn Olav (2012). Compartmented production and degradation of cAMP by beta-adrenergic, prostanoid and 5-HT4 receptors in CHF, visualized by FRET-based cAMP sensors. Full text in Research Archive
• Andressen, Kjetil Wessel; Dugstad, KS; Aronsen, Jan Magnus; Sjaastad, Ivar; Zaccolo, Manuela & Levy, Finn Olav (2011). Unraveling tight spatiotemporal regulation of cAMP-mediated inotropic effects using targeted FRET-based cAMP sensors. Full text in Research Archive
• Afzal, Faraz; Andressen, Kjetil Wessel; Mørk, Halvor Kjeang; Aronsen, Jon magnus; Moltzau, Lise Roman & Sjaastad, Ivar [Show all 10 contributors for this article] (2007). 5-HT4-mediated positive inotropic effect is regulated by phosphodiesterase 3 in failing rat heart and human ventricle. Journal of Molecular and Cellular Cardiology. ISSN 0022-2828. 42(6), p. S152–S152. Full text in Research Archive
• Andressen, Kjetil Wessel; Norum, Jens Henrik; Levy, Finn Olav & Krobert, Kurt Allen (2006). Activation of adenylyl cyclase in HEK293 cells by endogenous G(s)-coupled receptors is attenuated by 5-HT7 receptor expression. Journal of Pharmacological Sciences (JPS). ISSN 1347-8613. 101, p. 128–128. Full text in Research Archive
• Qvigstad, Eirik; Birkeland, Jon Arne; Sjaastad, Ivar; Brattelid, Trond; Andressen, Kjetil Wessel & Krobert, Kurt Allen [Show all 12 contributors for this article] (2005). Treatment of heart failure by blockade of ventricular myocardial serotonin receptors appearing in heart failure. Journal of Molecular and Cellular Cardiology. ISSN 0022-2828. 38, p. 1041–1041. Full text in Research Archive
• Andressen, Kjetil Wessel & Levy, Finn Olav (2008). The 5-HT₇ serotonin receptor : G protein preassociation and functional selectivity. Universitetet i Oslo. ISSN 9788280727473. Full text in Research Archive

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