Article
Neurosciences
Lei Wang, Douglas F. Covey, Gustav Akk, Alex S. Evers
Summary: Neurosteroids are endogenous modulators of GABA(A) receptors that regulate anxiety, pain, mood, and arousal. The 3-hydroxyl epimers, allopregnanolone (3 alpha-OH) and epi-allopregnanolone (3 beta-OH), have opposite effects on GABA(A) receptor function, acting as positive and negative allosteric modulators, respectively. A model is proposed to explain the actions of these neurosteroids based on their binding to specific sites on GABA(A) receptors, with the net functional effect being the sum of their independent effects at each site.
CURRENT NEUROPHARMACOLOGY
(2022)
Article
Endocrinology & Metabolism
Roshni Das, Gianna Ragagnin, Jessica Sjostedt, Maja Johansson, David Haage, Michael Druzin, Staffan Johansson, Torbjorn Backstrom
Summary: MPA acts as a positive modulator of specific GABAA receptor subtypes and increases responses to GABA in single cells from the hypothalamic area, indicating its potential role in cognitive processes and neural modulation.
PSYCHONEUROENDOCRINOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Hiroki Tateiwa, Satyanarayana M. Chintala, Ziwei Chen, Lei Wang, Fatima Amtashar, John Bracamontes, Allison L. Germann, Spencer R. Pierce, Douglas F. Covey, Gustav Akk, Alex S. Evers
Summary: This study aimed to determine the difference in enantioselectivity between allopregnanolone (ALLO) and pregnanolone (PREG) as positive allosteric modulators (PAMs) of GABA(A) receptors. The results revealed that the difference in enantioselectivity is due to the differential binding of ALLO and PREG to the intersubunit binding site.
Article
Pharmacology & Pharmacy
Spencer R. Pierce, Allison L. Germann, Joe Henry Steinbach, A. K. K. Gustav
Summary: This study demonstrates that inhibitory steroids pregnenolone sulfate and dehydroepiandrosterone sulfate act through a common interaction site by stabilizing a distinct non-conducting state.
MOLECULAR PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Hodaka Saito, Wakana Tachiura, Mizuki Nishimura, Makoto Shimizu, Ryuichiro Sato, Yoshio Yamauchi
Summary: Cholesterol metabolites, oxysterols, are essential in controlling cholesterol feedback. They regulate the activity of transcription factors SREBP-2 and LXR. The study investigates the role of endogenously synthesized oxysterols on SREBP-2 and LXR activity.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Johansen B. Amin, Miaomiao He, Ramesh Prasad, Xiaoling Leng, Huan-Xiang Zhou, Lonnie P. Wollmuth
Summary: NMDA receptors have two gates that are regulated by distinct subunits, with one gate mainly regulating single channel events and the other gate mainly regulating entry and exit from clusters. The unique kinetics of NMDARs contribute to their role in synaptic signaling, with clusters of rapid opening and closing separated by long silent periods.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Shiyan Chen, Jiamei Lian, Yueqing Su, Chao Deng
Summary: This study investigated the effects of adolescent risperidone treatment on GABA(A) receptors and AKT/GSK3 beta in the ventral tegmental area. The results showed that risperidone partially reversed the decreased expression of GAD2 and had differential effects on GABAergic neurotransmission and AKT-GSK3 beta signaling.
Article
Chemistry, Multidisciplinary
Rong Wang, Wenhan He, Xin Yi, Zhenkun Wu, Xia Chu, Jian-Hui Jiang
Summary: This article reports a novel design of a bioorthogonally inducible DNAzyme that is deactivated by site-specific installation of bioorthogonal caging groups, but restores the activity via a phosphine-triggered Staudinger reduction. The researchers performed a systematic screening and identified an inducible DNAzyme with very low leakage activity. This design achieved bioorthogonally controlled cleavage of exogenous and endogenous mRNA in live cells, and showed potential for on-demand gene therapy.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Neurosciences
Allison L. Germann, Spencer R. Pierce, Alex S. Evers, Joe Henry Steinbach, Gustav Akk
Summary: This study aims to investigate the sensitivity of the fitted IC50 and the properties of inhibitors to the activity level of the control response using computational models. The results indicate that the fitted IC50 of the inhibition curve is sensitive to the degree of activity of the control response, and the IC50 of inhibition varies depending on the mechanism of inhibition. The apparent potency of an inhibitor is inferred to depend on the activity level of the control response.
CURRENT NEUROPHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Allison L. Germann, Ariel B. Burbridge, Spencer R. Pierce, Gustav Akk
Summary: GABA(A) receptors play an important role in inhibitory neurotransmission in the brain. In this study, the functional properties of the rat alpha 1 beta 2 epsilon GABA(A) receptor were characterized. It was found that this receptor exhibits higher constitutive activity and reduced response to certain drugs. Surprisingly, amino acid substitutions in the epsilon subunit did not produce expected functional effects.
Article
Biochemistry & Molecular Biology
Spencer R. Pierce, Allison L. Germann, Gustav Akk
Summary: The study focused on the activation and modulation of the Cl- permeable GABA(A) receptor, revealing its sensitivity to various physiological compounds and their interactions as activators. The findings contribute to understanding how changes in endogenous agonists levels modulate receptor activity and cellular inhibition.
Article
Multidisciplinary Sciences
Heng Zhang, Jia-Jia Lin, Ya-Kai Xie, Xiu-Zu Song, Jia-Yi Sun, Bei-Lei Zhang, Yun-Kun Qi, Zhen-Zhong Xu, Fan Yang
Summary: The authors have engineered a peptide called s-RhTx as a positive allosteric modulator of the TRPV1 channel. It enhances the activity of TRPV1, allowing for reversible elimination of pain-sensing nerve terminals, providing long-lasting analgesia without affecting mice body temperature.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Konrad A. Szychowski, Bartosz Skora, Anna K. Wojtowicz
Summary: Epidemiological studies have shown that triclosan (TCS) can be found in the brain due to its widespread use as an antibacterial ingredient. One of the mechanisms of its action is the interaction with the aryl hydrocarbon receptor (AhR). In nerve cells, Sirt1 and Sirt3 act as cellular sensors and regulate metabolic processes. The aim of this study was to evaluate the effect of TCS on the production of neurosteroids in primary neural cortical neurons. The results showed that short and long exposure to TCS increased the expression of Sirt1 and Sirt3 proteins in response to AhR stimulation. However, prolonged exposure to TCS decreased the levels of neurosteroids in the cells.
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
(2022)
Article
Medicine, Research & Experimental
Teresa Faleschini, Nova Syafni, Heidi Luise Schulte, Aleksandra Garifulina, Steffen Hering, Laila Salmen Espindola, Matthias Hamburger
Summary: In a screening of Amazonian and Cerrado plant extracts, a hexane extract from Connarus tuberosus roots was found to enhance the GABA response in CHO cells expressing human GABAA receptors. The active compound was identified as connarin. Connarin's activity was not affected by flumazenil, but was increased by diazepam. It was also inhibited by pregnenolone sulfate and enhanced by allopregnanolone in CHO cells. In Xenopus laevis oocytes expressing human GABAA receptors, connarin potentiated GABA-induced currents, and its activation was blocked by increasing concentrations of PREGS.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Biochemistry & Molecular Biology
Spencer R. Pierce, Allison L. Germann, Sophia Q. Xu, Saumith L. Menon, Marcelo O. Ortells, Hugo R. Arias, Gustav Akk
Summary: In this study, mutational analysis was used to investigate the involvement and contributions of individual intersubunit interfaces to the modulation of the alpha 1 beta 2 gamma 2L GABA(A) receptor by NS-1738 and PAM-2. The results showed that mutations to any single interface can completely abolish the potentiation by the alpha 7-PAMs. The findings are discussed in terms of energetic additivity and interactions between the different binding sites.
Article
Biochemistry & Molecular Biology
Melissa M. Budelier, Wayland W. L. Cheng, Zi-Wei Chen, John R. Bracamontes, Yusuke Sugasawa, Kathiresan Krishnan, Laurel Mydock-McGrane, Douglas F. Covey, Alex S. Evers
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
(2019)
Article
Biochemistry & Molecular Biology
Zi-Wei Chen, John R. Bracamontes, Melissa M. Budelier, Allison L. Germann, Daniel J. Shin, Krishnan Kathiresan, Ming-Xing Qian, Brad Manion, Wayland W. L. Cheng, David E. Reichert, Gustav Akk, Douglas F. Covey, Alex S. Evers
Article
Nanoscience & Nanotechnology
Gyu Seong Heo, Yongfeng Zhao, Deborah Sultan, Xiaohui Zhang, Lisa Detering, Hannah P. Luehmann, Xiangyu Zhang, Richen Li, Ankur Choksi, Savannah Sharp, Sidney Levingston, Tina Primeau, David E. Reichert, Guorong Sun, Babak Razani, Shunqiang Li, Katherine N. Weilbaecher, Farrokh Dehdashti, Karen L. Wooley, Yongjian Liu
ACS APPLIED MATERIALS & INTERFACES
(2019)
Article
Biochemistry & Molecular Biology
Yusuke Sugasawa, John R. Bracamontes, Kathiresan Krishnan, Douglas F. Covey, David E. Reichert, Gustav Akk, Qiang Chen, Pei Tang, Alex S. Evers, Wayland W. L. Cheng
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
(2019)
Article
Chemistry, Analytical
John T. Petroff, Ailing Tong, Lawrence J. Chen, Gregory T. Dekoster, Farha Khan, Jeff Abramson, Carl Frieden, Wayland W. L. Cheng
ANALYTICAL CHEMISTRY
(2020)
Article
Pharmacology & Pharmacy
Gustav Akk, Allison L. Germann, Yusuke Sugasawa, Spencer R. Pierce, Alex S. Evers, Joe Henry Steinbach
MOLECULAR PHARMACOLOGY
(2020)
Article
Pharmacology & Pharmacy
Allison L. Germann, David E. Reichert, Ariel B. Burbridge, Spencer R. Pierce, Alex S. Evers, Joe Henry Steinbach, Gustav Akk
MOLECULAR PHARMACOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Kathiresan Krishnan, Mingxing Qian, McKenna Feltes, Zi-Wei Chen, Sarah Gale, Lei Wang, Yusuke Sugasawa, David E. Reichert, Jean E. Schaffer, Daniel S. Ory, Alex S. Evers, Douglas F. Covey
Summary: Cholesterol analogues containing aliphatic diazirine or TPD groups were used as photoaffinity labeling reagents to study cholesterol binding sites on GLIC. The probes showed differences in photolabeling efficiencies and residues identified, indicating complementary information provided by the two classes of probes. Photoaffinity labeling using these reagents in mammalian cell membranes revealed differences in the pattern of labeled proteins, highlighting their utility in future studies of cholesterol biology.
ACS CHEMICAL BIOLOGY
(2021)
Article
Pharmacology & Pharmacy
Allison L. Germann, Spencer R. Pierce, Hiroki Tateiwa, Yusuke Sugasawa, David E. Reichert, Alex S. Evers, Joe Henry Steinbach, Gustav Akk
Summary: Previous work has identified three distinct binding sites for potentiating steroids in the heteromeric GABA(A) receptor, with mutations in these sites showing independent and additive effects. The findings suggest that mutations in sites I and II have energetically additive effects, while mutations in site III do not affect potentiation by the steroid. The results indicate that steroid actions at each binding site are independent.
MOLECULAR PHARMACOLOGY
(2021)
Article
Physiology
Edwin J. Baldelomar, David E. Reichert, Kooresh Shoghi, Scott C. Beeman, Jennifer R. Charlton, Lori Strong, Nikki Fettig, Amanda Klaas, Kevin M. Bennett
Summary: The research presented a novel contrast agent, RadioCF, for mapping functioning glomeruli in the kidney using PET technology. RadioCF-PET can accurately distinguish kidneys between healthy mice and those with low nephron mass, with potential for clinical translation.
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
(2021)