Article
Neurosciences
Dan L. McElroy, Andrew J. Roebuck, Gavin A. Scott, Quentin Greba, Sumanta Garai, Eileen M. Denovan-Wright, Ganesh A. Thakur, Robert B. Laprairie, John G. Howland
Summary: The study compared the effects of CB1R positive allosteric modulator GAT211 and THC on psychiatric behavioral phenotypes in rats following acute MK-801 treatment. GAT211 was found to limit dopamine D2 receptor-mediated extracellular regulated kinase (ERK) phosphorylation and reduce locomotor activity, suggesting its potential as an antipsychotic agent.
PSYCHOPHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Mehek Ningoo, Leigh D. Plant, Anna Greka, Diomedes E. Logothetis
Summary: TRPC5 ion channels, expressed in the brain and kidney, are promising therapeutic targets for diseases like focal segmental glomerular sclerosis. The role of PIP2 in controlling TRPC5 channel activity through gating rather than cell surface density, influenced by DAG and lanthanide ions, provides new opportunities for targeted therapies in chronic kidney diseases.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Sumanta Garai, Luciana M. Leo, Anna-Maria Szczesniak, Dow P. Hurst, Peter C. Schaffer, Ayat Zagzoog, Tallan Black, Jeffrey R. Deschamps, Elke Miess, Stefan Schulz, David R. Janero, Alex Straiker, Roger G. Pertwee, Mary E. Abood, Melanie E. M. Kelly, Patricia H. Reggio, Robert B. Laprairie, Ganesh A. Thakur
Summary: By introducing a methyl group at the a-position of the nitro group, the greater potency and efficacy of the 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator was achieved, offering safer therapeutic candidates for glaucoma and potentially other diseases. The diastereoselective CB1R-allosteric modulator interaction was demonstrated for the first time, with one enantiomer showing improved potency and the other biased towards specific signaling pathways. Exploiting G-protein biased CB1R-allosteric modulation shows promise for developing more effective and targeted treatments.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Nanoscience & Nanotechnology
Zonglin Gu, Austin M. Baggetta, Yu Chong, Leigh D. Plant, Xuan-Yu Meng, Ruhong Zhou
Summary: Graphene quantum dots interact with potassium-ion channels in a multifaceted manner, either enhancing or blocking channel currents, or having no apparent impact on certain channels. This multifaceted regulation could potentially lead to the design of new nanomaterial-based channel modulators.
ACS APPLIED MATERIALS & INTERFACES
(2021)
Article
Neurosciences
Andrew J. Roebuck, Quentin Greba, Anna-Maria Smolyakova, Mariam Alaverdashvili, Wendie N. Marks, Sumanta Garai, Samantha L. Baglot, Gavin Petrie, Stuart M. Cain, Terrance P. Snutch, Ganesh A. Thakur, Matthew N. Hill, John G. Howland, Robert B. Laprairie
Summary: Research suggests that current treatments for CAE are not always effective, and modulation of certain cannabinoids and the CB1R receptor may offer more promising pharmacological treatments for absence seizures.
Article
Neurosciences
Ayman K. Hamouda, Malia R. Bautista, Lois S. Akinola, Yasmin Alkhlaif, Asti Jackson, Moriah Carper, Wisam B. Toma, Sumanta Garai, Yen-Chu Chen, Ganesh A. Thakur, Christie D. Fowler, M. Imad Damaj
Summary: The high sensitivity (HS) nAChR isoforms play a more prevalent role in mediating various brain functions and behavioral effects associated with nicotine use, while the low sensitivity (LS) nAChR isoforms have a limited impact on modulating body temperature and nociceptive responses. These findings will aid in the development of more selective and efficacious nAChR-based therapeutics for nicotine addiction treatment.
Article
Clinical Neurology
Timothy J. Onofrychuk, Shuang Cai, Dan L. McElroy, Andrew J. Roebuck, Quentin Greba, Sumanta Garai, Ganesh A. Thakur, Robert B. Laprairie, John G. Howland
Summary: The altered interactions between endocannabinoid and glutamate signaling may play a role in the pathophysiology of schizophrenia and acute psychosis. In this study, the effects of a cannabinoid receptor 1 positive allosteric modulator on a rodent model of acute psychosis induced by MK-801 were examined, showing that acute MK-801 significantly impacted behavioral measures of attention and impulsivity.
PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY
(2021)
Article
Biochemistry & Molecular Biology
Sumanta Garai, Peter C. Schaffer, Robert B. Laprairie, David R. Janero, Roger G. Pertwee, Alex Straiker, Ganesh A. Thakur
Summary: This study focused on developing allosteric modulators for CB1R, with modifications at the C2 position of the indole ring within GAT211 to improve pharmacological profile. Furan and thiophene rings were found to be well-tolerated and effectively bind to hCB1R. The novel ligands reported in this study offer guidance for future development of CB1R allosteric modulators.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Xiuxiu Wang, Nan Yang, Juan Su, Chenchen Wu, Shengtang Liu, Lei Chang, Leigh D. Plant, Xuanyu Meng
Summary: This study provides insights into the interaction between Gd@C-82(OH)(22) and hVDAC1, revealing the potential of this nanodrug to inhibit cancer cell growth and metastasis.
Article
Multidisciplinary Sciences
Valentina Corradi, Anna N. Bukiya, Williams E. Miranda, Meng Cui, Leigh D. Plant, Diomedes E. Logothetis, D. Peter Tieleman, Sergei Y. Noskov, Avia Rosenhouse-Dantsker
Summary: This study reveals the molecular mechanism of cholesterol's effect on ion channel activity. Through mutagenesis and simulation experiments on the Kir3.4 channel, researchers identified a molecular switch that controls the regulation of the channel by cholesterol. This switch changes the conformation of the channel, leading to different effects of cholesterol on the channel's activity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Pharmacology & Pharmacy
Paulo A. De Oliveira, Estefania Moreno, Nil Casajuana-Martin, Veronica Casado-Anguera, Ning-Sheng Cai, Gisela Andrea Camacho-Hernandez, Hu Zhu, Alessandro Bonifazi, Matthew D. Hall, David Weinshenker, Amy Hauck Newman, Diomedes E. Logothetis, Vicent Casado, Leigh D. Plant, Leonardo Pardo, Sergi Ferre
Summary: Recent studies suggest that the heteromers of mu-opioid receptors (MORs) and galanin Gal(1) receptors (Gal(1)Rs) in the mesencephalon play a role in mediating the dopaminergic effects of opioids. This study provides evidence for a predominant homodimeric structure of MOR and Gal(1)R when expressed individually and for their preference to form functional heterotetramers when co-expressed. The results show that this heteromerization leads to a change in G-protein coupling, providing a framework for Gs-Gi antagonist interaction.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Physiology
Kirin D. Gada, Jordie M. Kamuene, Aishwarya Chandrashekar, R. Charles Kissell, Anne K. Yauch, Leigh D. Plant
Summary: Voltage-gated sodium channels play a crucial role in the activation and inactivation of excitable cells. The gating behavior of these channels is tightly regulated by the phospholipid PI(4,5)P-2. In this study, the researchers used optogenetics to deactivate PI(4,5)P-2 and found that it shifts the voltage-dependent gating of Na(V)1.4 channels to more hyperpolarized potentials, increases late currents, and accelerates recovery from inactivation. These findings suggest that PI(4,5)P-2 negatively regulates the gating behavior of Na(V)1.4 channels.
JOURNAL OF GENERAL PHYSIOLOGY
(2023)
Article
Biology
Oron Kotler, Yana Khrapunsky, Arik Shvartsman, Hui Dai, Leigh D. Plant, Steven A. N. Goldstein, Ilya Fleidervish
Summary: Voltage-gated sodium channels in axon initial segments have distinct roles in regulating action potentials of cortical pyramidal neurons. While Na(V)1.6 promotes AP initiation and forward propagation, Na(V)1.2 facilitates backpropagation to the soma. This study demonstrates that the SUMO pathway modulates Na+ channels at the initial segments, increasing neuronal gain and backpropagation speed by SUMOylation of Na(V)1.2. These findings highlight the prominent role of SUMOylation in synaptic integration and plasticity.
Article
Biochemical Research Methods
Kirin D. Gada, Yu Xu, Brenda T. Winn, Meghan Masotti, Takeharu Kawano, Heikki Vaananen, Leigh D. Plant
Summary: Here, we present a protocol for optogenetic dephosphorylation of PI(4,5)P2 at the plasma membrane of Xenopus laevis oocytes. Blue light illumination is used to induce dephosphorylation, and the potassium channel current responses are assessed through simultaneous electrophysiological recording.
Article
Biology
Kirin D. Gada, Jordie M. Kamuene, Takeharu Kawano, Leigh D. Plant
Summary: The cell surfaceome plays a crucial role in biology, but the identification and regulation of proteins on the cell membrane remains challenging. TIRFM is a precise and effective technique that helps to locate proteins on the cell membrane by limiting image depth and improving signal-to-noise ratio.