negative modulator
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2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Fabio Simeoni ◽  
Aleksandra Skirycz ◽  
Laura Simoni ◽  
Giulia Castorina ◽  
Leonardo Perez de Souza ◽  
...  

AbstractStomata are epidermal pores formed by pairs of specialized guard cells, which regulate gas exchanges between the plant and the atmosphere. Modulation of transcription has emerged as an important level of regulation of stomatal activity. The AtMYB60 transcription factor was previously identified as a positive regulator of stomatal opening, although the details of its function remain unknown. Here, we propose a role for AtMYB60 as a negative modulator of oxylipins synthesis in stomata. The atmyb60-1 mutant shows reduced stomatal opening and accumulates increased levels of 12-oxo-phytodienoic acid (12-OPDA), jasmonic acid (JA) and jasmonoyl-l-isoleucine (JA-Ile) in guard cells. We provide evidence that 12-OPDA triggers stomatal closure independently of JA and cooperatively with abscisic acid (ABA) in atmyb60-1. Our study highlights the relevance of oxylipins metabolism in stomatal regulation and indicates AtMYB60 as transcriptional integrator of ABA and oxylipins responses in guard cells.


Author(s):  
Dmitrii Kulbatskii ◽  
Zakhar Shenkarev ◽  
Maxim Bychkov ◽  
Eugene Loktyushov ◽  
Mikhail Shulepko ◽  
...  

Lypd6 is a GPI-tethered protein from the Ly-6/uPAR family expressed in the brain. Lypd6 enhances the Wnt/β-catenin signaling, although its action on nicotinic acetylcholine receptors (nAChRs) have been also proposed. To investigate a cholinergic activity of Lypd6, we studied a recombinant water-soluble variant of the human protein (ws-Lypd6) containing isolated “three-finger” LU-domain. Experiments at different nAChR subtypes expressed in Xenopus oocytes revealed the negative allosteric modulatory activity of ws-Lypd6. Ws-Lypd6 inhibited ACh-evoked currents at α3β4- and α7-nAChRs with IC50 of ∼35 and 10 μM, respectively, and the maximal amplitude of inhibition of 30–50%. EC50 of ACh at α3β4-nAChRs (∼30 μM) was not changed in the presence of 35 μM ws-Lypd6, while the maximal amplitude of ACh-evoked current was reduced by ∼20%. Ws-Lypd6 did not elicit currents through nAChRs in the absence of ACh. Application of 1 μM ws-Lypd6 significantly inhibited (up to ∼28%) choline-evoked current at α7-nAChRs in rat hippocampal slices. Similar to snake neurotoxin α-bungarotoxin, ws-Lypd6 suppressed the long-term potentiation (LTP) in mouse hippocampal slices. Colocalization of endogenous GPI-tethered Lypd6 with α3β4- and α7-nAChRs was detected in primary cortical and hippocampal neurons. Ws-Lypd6 interaction with the extracellular domain of α7-nAChR was modeled using the ensemble protein-protein docking protocol. The interaction of all three Lypd6 loops (“fingers”) with the entrance to the orthosteric ligand-binding site and the loop C of the primary receptor subunit was predicted. The results obtained allow us to consider Lypd6 as the endogenous negative modulator involved in the regulation of the cholinergic system in the brain.


2021 ◽  
Author(s):  
John Smith Del Rosario ◽  
Matthew Gabrielle ◽  
Yevgen Yudin ◽  
Tibor Rohacs

Mechanically activated Piezo2 channels are key mediators of light touch and proprioception in mice and humans. Relatively little is known about what other proteins regulate Piezo2 activity in a cellular context. TACAN (TMEM120A) was proposed to act as a high threshold mechanically activated ion channel in nociceptive dorsal root ganglion (DRG) neurons. Here we find that TACAN co-expression robustly reduced mechanically activated Piezo2 currents, but did not inhibit mechanically activated Piezo1 and TREK1 currents. TACAN co-expression did not affect cell surface expression of either Piezo1 or Piezo2 and did not have major effects on the cortical actin or tubulin cytoskeleton. TACAN expression alone did not result in the appearance of mechanically activated currents above background. In addition, TACAN and Piezo2 expression in DRG neurons overlapped, and siRNA mediated knockdown of TACAN did not decrease the proportion of slowly adapting mechanically activated currents, but resulted in an increased proportion of rapidly adapting currents. Our data do not support TACAN being a mechanically activated ion channel, and identify it as a negative modulator of Piezo2 channel activity.


2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 498-498
Author(s):  
Caroline Harmon ◽  
Daiyong Deng ◽  
Paul Breslin

Abstract Objectives The objective of this study was to determine the effect of 5’-ribonucleotides on the absolute detection threshold of L-glutamate.  We hypothesized that the addition of these and other ribonucleotides would decrease the absolute detection threshold of L-glutamic acid potassium salt (MPG) when in admixture; thus, sensitivity to glutamate would be increased in their presence. Methods The absolute detection thresholds of MPG were measured in 17 healthy volunteers and compared to the detection threshold for MPG in the presence of a background level of 5’ ribonucleotide guanosine-, inosine-, adenosine-, uridine-, or cytosine-monophosphate disodium salt (3 mM). Results The average detection threshold of MPG was 1.90 × 10−03 M. We found the additions of inosine 5'-monophosphate (IMP), guanosine 5'-monophosphate (GMP), and adenosine 5'-monophosphate (AMP), lowered the MPG detection threshold for every subject and were statistically significant (p < 0.001), suggesting they are positive modulators of glutamate taste. IMP was the most robust enhancer of MPG detection and decreased the detection threshold by a factor of 41.4 to a concentration 4.60 × 10−05 M. GMP and AMP decreased the detection threshold of glutamate by a factor of 27.3 and 8.2, respectively. UMP and CMP, however, yielded different results. Interestingly, CMP raised glutamate detection thresholds in 60% of subjects, suggesting it is an inhibitor or negative modulator of glutamate taste in humans.  The addition of UMP to the MPG solution produced mixed results and did not significantly modulate the detection of MPG. The rank order of effects on increasing sensitivity to glutamate was IMP > GMP > AMP, whereas CMP appeared to decrease sensitivity to glutamate. Conclusions Ribonucleotides are modulators of the  detection threshold of glutamate.Some, such as IMP, are enhancers of glutamate taste, and others, such as CMP, appear to be suppressors of glutamate taste. This may be due to positive and negative allosteric modulation, respectively, of the T1R1/T1R3 glutamate receptor in the oral cavity. Funding Sources P.A.S.B. was funded by by NIH NIDCD RO1 014286 as Co-PI and NJ Hatch Project No.NJ14120.


2020 ◽  
Vol 13 ◽  
pp. 100280
Author(s):  
A. Longaretti ◽  
C. Forastieri ◽  
E. Toffolo ◽  
L. Caffino ◽  
A. Locarno ◽  
...  

2020 ◽  
Vol 79 ◽  
pp. 101035 ◽  
Author(s):  
Deepankumar Shanmugamprema ◽  
Karthi Muthuswamy ◽  
Gowtham Subramanian ◽  
Vinithra Ponnusamy ◽  
Vasanth Krishnan ◽  
...  

2020 ◽  
Vol 48 (14) ◽  
pp. 7609-7622 ◽  
Author(s):  
Cassandra K Hayne ◽  
Casey A Schmidt ◽  
Maira I Haque ◽  
A Gregory Matera ◽  
Robin E Stanley

Abstract The splicing of tRNA introns is a critical step in pre-tRNA maturation. In archaea and eukaryotes, tRNA intron removal is catalyzed by the tRNA splicing endonuclease (TSEN) complex. Eukaryotic TSEN is comprised of four core subunits (TSEN54, TSEN2, TSEN34 and TSEN15). The human TSEN complex additionally co-purifies with the polynucleotide kinase CLP1; however, CLP1’s role in tRNA splicing remains unclear. Mutations in genes encoding all four TSEN subunits, as well as CLP1, are known to cause neurodegenerative disorders, yet the mechanisms underlying the pathogenesis of these disorders are unknown. Here, we developed a recombinant system that produces active TSEN complex. Co-expression of all four TSEN subunits is required for efficient formation and function of the complex. We show that human CLP1 associates with the active TSEN complex, but is not required for tRNA intron cleavage in vitro. Moreover, RNAi knockdown of the Drosophila CLP1 orthologue, cbc, promotes biogenesis of mature tRNAs and circularized tRNA introns (tricRNAs) in vivo. Collectively, these and other findings suggest that CLP1/cbc plays a regulatory role in tRNA splicing by serving as a negative modulator of the direct tRNA ligation pathway in animal cells.


2020 ◽  
Vol 27 (11) ◽  
pp. 3065-3081 ◽  
Author(s):  
Jinho Seo ◽  
Daehyeon Seong ◽  
Young Woo Nam ◽  
Chi Hyun Hwang ◽  
Seung Ri Lee ◽  
...  

Abstract Necroptosis is a form of regulated cell death caused by formation of the necrosome complex. However, the factors modulating this process and the systemic pathophysiological effects of necroptosis are yet to be understood. Here, we identified that Beclin 1 functions as an anti-necroptosis factor by being recruited into the necrosome complex upon treatment with TNFα, Smac mimetic, and pan-caspase inhibitor and by repressing MLKL oligomerisation, thus preventing the disruption of the plasma membrane. Cells ablated or knocked-out for Beclin 1 become sensitised to necroptosis in an autophagy-independent manner without affecting the necrosome formation itself. Interestingly, the recruitment of Beclin 1 into the necrosome complex is dependent on the activation and phosphorylation of MLKL. Biochemically, the coiled-coil domain (CCD) of Beclin 1 binds to the CCD of MLKL, which restrains the oligomerisation of phosphorylated MLKL. Finally, Beclin 1 depletion was found to promote necroptosis in leukaemia cells and enhance regression of xenografted-tumour upon treatment with Smac mimetics and caspase inhibitors. These results suggest that Beclin 1 functions as a negative regulator in the execution of necroptosis by suppressing MLKL oligomerisation.


2020 ◽  
Vol 11 ◽  
Author(s):  
Bo Hjorth Bentzen ◽  
Sofia Hammami Bomholtz ◽  
Rafel Simó-Vicens ◽  
Lasse Folkersen ◽  
Lea Abildgaard ◽  
...  

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