Article
Multidisciplinary Sciences
Zheng Fang Yang, Pankaj Panwar, Ciaran R. McFarlane, Wietske E. Tuinte, Marta Campiglio, Filip Van Petegem
Summary: Junctophilins (JPH) are proteins that connect the plasma membrane and the endoplasmic or sarcoplasmic reticulum, facilitating communication between proteins in different membranes. This study presents crystal structures of two JPH isoforms, revealing their importance in muscle excitation-contraction coupling. Various mutations in JPH2 and the L-type calcium channel affect their interaction and have been linked to cardiomyopathy and cardiac arrhythmia, respectively.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biology
Xueyong Wang, Murad Nawaz, Chris DuPont, Jessica H. Myers, Steve Ra Burke, Roger A. Bannister, Brent D. Foy, Andrew A. Voss, Mark M. Rich
Summary: Excitation-contraction coupling is the process of converting electrical excitation of muscle into force generation. Depolarization of skeletal muscle can lead to failure of ECC, specifically the failure to generate calcium transients. Different AP properties, such as AP peak and AP integral, play important roles in different steps of ECC, including AP conduction and calcium release.
Article
Multidisciplinary Sciences
Lei Yang, Rong-Chang Li, Bin Xiang, Yi-Chen Li, Li-Peng Wang, Yun-Bo Guo, Jing-Hui Liang, Xiao-Ting Wang, Tingting Hou, Xin Xing, Zeng-Quan Zhou, Haihong Ye, Ren-Qing Feng, Edward G. Lakatta, Zhen Chai, Shi-Qiang Wang
Summary: The contraction of heart cells is regulated by the signaling interaction between LCCs and RyRs, which is influenced by the nanodistance between JPH2 in the SR and CAV3 in the TT. Our study revealed that SRF and myocardin concurrently regulate the expression of JPH2 and CAV3, leading to enhanced efficiency of LCC-RyR signaling and compensation for LCC down-regulation during hibernation, maintaining heart power and avoiding calcium overload.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Cardiac & Cardiovascular Systems
Natalia S. Torres
Summary: This study demonstrates that the skeletal Na channel isoform (Na(v)1.4) is the primary isoform involved in the priming mechanism in rabbit ventricular cells, regulating the efficiency of excitation-contraction coupling by activating reverse-mode NCX. The results suggest that Na(v)1.4 plays a crucial role in modulating the calcium handling properties during EC coupling in cardiomyocytes.
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
(2021)
Article
Multidisciplinary Sciences
Nicholas C. Vierra, Samantha C. O'Dwyer, Collin Matsumoto, L. Fernando Santana, James S. Trimmer
Summary: In mammalian brain neurons, membrane depolarization triggers Ca2+ influx through voltage-gated Ca2+ channels, leading to diverse cellular responses, including gene expression. The L-type Ca2+ channels in neuronal soma and dendrites play a key role in this process. The organization of signaling complexes by Kv2.1 at endoplasmic reticulum-plasma membrane junctions enhances the clustering and activity of Cav1.2 channels, impacting somatic Ca2+ signals and excitation-transcription coupling.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Cell Biology
Noopur Dave, Kaice LaFavers, Gustavo Arrizabalaga
Summary: Calcium signaling plays a crucial role in the regulation of the obligate intracellular parasite Toxoplasma gondii, and a novel EF-hand domain-containing protein, TgEFP1, has been identified in this calcium homeostasis network, localizing to the PLV/ELC and PV. Knockout of TgEFP1 results in faster parasite propagation, hypersensitivity to calcium ionophore-induced egress, and premature natural egress.
Review
Neurosciences
Byoung Ju Lee, Che Ho Yang, Seung Yeon Lee, Suk-Ho Lee, Yujin Kim, Won-Kyung Ho
Summary: The coupling distance between VGCCs and synaptic vesicles determines the VGCC dependence of spontaneous release at synapses, with tightly coupled synapses showing significant VGCC contribution while loosely coupled synapses have minimal VGCC involvement.
PROGRESS IN NEUROBIOLOGY
(2022)
Review
Toxicology
Joshua A. Keefe, Oliver M. Moore, Kevin S. Ho, Xander H. T. Wehrens
Summary: This review provides a comprehensive overview of the roles of Ca2+-handling proteins in healthy cardiac function and the mechanisms by which mutations in these proteins contribute to inherited arrhythmias. The major Ca2+ channels and Ca2+-sensitive regulatory proteins involved in cardiac excitation-contraction coupling are discussed, with special emphasis on the function of the RyR2 macromolecular complex. Inherited arrhythmia disorders caused by mutations in Ca2+-handling proteins are also discussed.
ARCHIVES OF TOXICOLOGY
(2023)
Article
Biology
Eider Nunez, Frederick Jones, Arantza Muguruza-Montero, Janire Urrutia, Alejandra Aguado, Covadonga Malo, Ganeko Bernardo-Seisdedos, Carmen Domene, Oscar Millet, Nikita Gamper, Alvaro Villarroel, Henry M. Colecraft
Summary: Neuronal K(V)7 channels are highly sensitive to reactive oxygen species, and the S2S3 linker of the voltage sensor plays a crucial role in redox modulation of the channels. Recent structural studies have revealed interactions between this linker and the Ca2+-binding loop of calmodulin, specifically the EF3 hand, which is essential for the signaling. Disrupting Ca2+ binding to EF3 abolishes the oxidation-induced enhancement of K(V)7.4 currents. Furthermore, the loading of EF3 with Ca2+ is critical for the reorientation of the AB fork, which translates the Ca2+ signals.
Article
Cell Biology
Lucile Yart, Maud Frieden, Stephane Konig, Marie Cohen, Begona Martinez de Tejada
Summary: Nifedipine, an L-type voltage-gated Ca2+ channel blocker, is effective in reducing uterine contractions, but its efficacy is limited over time and may be ineffective in preventing preterm birth. Research has shown that nifedipine has different effects on different types of myometrial tissues, with potential involvement of TRPC channels in its pro-contractile effect.
JOURNAL OF CELLULAR PHYSIOLOGY
(2022)
Review
Physiology
Pura Bolanos, Juan C. Calderon
Summary: The excitation-contraction coupling in skeletal muscle is a crucial link between membrane excitation and mechanical contraction mediated by Ca2+, involving multiple mechanisms of Ca2+ release and recycling.
FRONTIERS IN PHYSIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Guillermo Avila
Summary: Fluorofenidone (AKF-PD) is a compound that inhibits fibrosis and inflammation. It has been shown to enhance cell contractility and Ca2+ channel activity in cardiac myocytes, suggesting potential therapeutic effects for cardiac diseases.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Bill Z. Jia, Yitong Qi, J. David Wong-Campos, Sean G. Megason, Adam E. Cohen
Summary: This study captured the first heartbeat of a zebrafish and analyzed the development of cardiac excitability and conduction around this event. The results showed how the gradual development of single-cell bioelectrical properties produces a consistent tissue-scale transition from quiescence to coordinated beating.
Article
Multidisciplinary Sciences
Bill Z. Jia, Yitong Qi, J. David Wong-Campos, Sean G. Megason, Adam E. Cohen
Summary: This study captured the first heartbeat of a zebrafish and analyzed the development of cardiac excitability and conduction around this event. The results showed that the transition from quiescence to coordinated beating is a gradual and asynchronous process, driven by the development of single-cell bioelectrical properties.
Article
Neurosciences
Daiki Watanabe, Ryo Ikegami, Yutaka Kano
Summary: This study investigated the mechanisms underlying faster force recovery from eccentric contractions in female mice compared to male mice. Superior mitochondrial responses and the contribution of estrogen were found to play a significant role in the faster recovery of force in females. These findings highlight the importance of mitochondrial function and estrogen in sex differences in force recovery.
JOURNAL OF PHYSIOLOGY-LONDON
(2021)
Article
Cell Biology
Heidi Espadas-Alvarez, Jacqueline Martinez-Rendon, Isabel Larre, Arturo Matamoros-Volante, Tatiana Romero-Garcia, Tamara Rosenbaum, Angelica Rueda, Refugio Garcia-Villegas
Summary: TRPV4 channel functions in the nucleus, inhibiting the transcriptional activity of beta-catenin through a direct interaction, and may regulate differentiation in various cellular contexts.
JOURNAL OF CELLULAR PHYSIOLOGY
(2021)
Review
Pharmacology & Pharmacy
Luciana Mosca, Andrea Ilari, Francesco Fazi, Yehuda G. Assaraf, Gianni Colotti
Summary: Taxanes have been widely used as microtubule-targeting antitumor agents since 1984, showing impacts on key molecular mechanisms and cellular processes in cancer treatment. Research into the diverse effects and molecular mechanisms of taxanes may lead to more rational and efficacious applications, as well as novel strategies to overcome drug resistance in cancer therapy.
DRUG RESISTANCE UPDATES
(2021)
Article
Biochemistry & Molecular Biology
Theo Battista, Gianmarco Pascarella, David Sasah Staid, Gianni Colotti, Jessica Rosati, Annarita Fiorillo, Alessia Casamassa, Angelo Luigi Vescovi, Barbara Giabbai, Marta Stefania Semrau, Sergio Fanelli, Paola Storici, Ferdinando Squitieri, Veronica Morea, Andrea Ilari
Summary: The study utilized a drug repositioning strategy to identify six drugs that can directly bind sigma 1R and improve the growth of cells from Huntington disease patients. These drugs have shown efficacy in providing new therapeutic tools against HD, offering hope for future treatments.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Valerio Chiarini, Annarita Fiorillo, Serena Camerini, Marco Crescenzi, Shin Nakamura, Theo Battista, Leonardo Guidoni, Gianni Colotti, Andrea Ilari
Summary: The study revealed that zinc ion can activate the protein splicing of BIL2, leading to ubiquitination through the formation of a covalent isopeptide bond. Additionally, ubiquitination of T.thRas-GTPase was found to stabilize the protein's active state.
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
(2021)
Article
Biochemistry & Molecular Biology
Anna Barile, Theo Battista, Annarita Fiorillo, Martino Luigi di Salvo, Francesco Malatesta, Angela Tramonti, Andrea Ilari, Roberto Contestabile
Summary: PLP, the active form of vitamin B6, is crucial in metabolism as an enzyme cofactor. In Escherichia coli, PNPO catalyzes PLP formation and is inhibited by the same molecule through allosteric regulation. Crystallographic studies identified the allosteric site of PLP on PNPO, and mutagenesis of the arginine cage can modulate the enzyme's allosteric properties.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Review
Physiology
Almudena Val-Blasco, Marta Gil-Fernandez, Angelica Rueda, Laetitia Pereira, Carmen Delgado, Tarik Smani, Gema Ruiz Hurtado, Maria Fernandez-Velasco
Summary: This review summarizes key findings related to Ca2+ mishandling in heart failure (HF), highlighting the increasing focus on identifying new targets and their role in disease progression. Recent studies have identified potential targets in three major emerging areas involved in regulating Ca2+ handling, contributing to the understanding of HF progression.
Article
Health Care Sciences & Services
Annarita Fiorillo, Veronica Morea, Gianni Colotti, Andrea Ilari
Summary: Huntington Disease is a lethal neurodegenerative disorder caused by the abnormal expansion of the HTT gene, and current research suggests that degrading mHtt through the ubiquitin-proteasome system plays a more crucial role in delaying disease progression. PROTACs, which can target specific E3 ubiquitin ligases, may be a promising strategy for Huntington Disease therapy.
JOURNAL OF PERSONALIZED MEDICINE
(2021)
Review
Endocrinology & Metabolism
Pamela Gaitan-Gonzalez, Rommel Sanchez-Hernandez, Jose-Antonio Arias-Montano, Angelica Rueda
Summary: Metabolic syndrome is a pre-diabetic state characterized by insulin resistance, visceral fat accumulation, and dyslipidemias, which increase the risk for developing cardiovascular disease. Increased synergistic tone in metabolic syndrome may contribute to the onset of pre-diabetic cardiomyopathy. The alterations in protein kinase A and Ca2+/calmodulin-dependent protein kinase II play important roles in functional responses mediated by beta(1)-adrenoceptors in pre-diabetes.
WORLD JOURNAL OF DIABETES
(2021)
Article
Physiology
Rogelio Salazar-Enciso, Agustin Guerrero-Hernandez, Ana M. Gomez, Jean-Pierre Benitah, Angelica Rueda
Summary: In this study, it was found that short-term exposure to ALDO can upregulate the expression of Ca(v)1.2 in rat MAs, increase the SR Ca2+ load, and Ca2+ spark and STOC frequencies. ALDO treatment also significantly increased the expression levels of the SERCA pump, which countered the augmented Ca(v)1.2-mediated Ca2+ influx.
FRONTIERS IN PHYSIOLOGY
(2022)
Article
Chemistry, Medicinal
Theo Battista, Stefano Federico, Simone Brogi, Luca Pozzetti, Tuhina Khan, Stefania Butini, Anna Ramunno, Eleonora Fiorentino, Stefania Orsini, Trentina Di Muccio, Annarita Fiorillo, Cecile Exertier, Daniel Di Risola, Andrea Ilari, Giuseppe Campiani, Gianni Colotti, Sandra Gemma
Summary: Leishmania spp. is a significant public health issue, and developing better therapeutic drugs is urgently needed. This study optimized a novel class of Leishmania inhibitors through various approaches and identified potent and selective compounds that could be used for treating leishmaniasis and related diseases.
ACS INFECTIOUS DISEASES
(2022)
Article
Biochemistry & Molecular Biology
Annarita Fiorillo, Gianni Colotti, Cecile Exertier, Anastasia Liuzzi, Francesca Seghetti, Alessandra Salerno, Jessica Caciolla, Andrea Ilari
Summary: Trypanothione reductase (TR) plays a key role in the redox homeostasis of trypanosomatid parasites and is essential for their survival in the oxidative environment. We conducted a fragment-based crystal screening and identified 12 new ligands binding to five different sites, including an allosteric pocket named the doorstop pocket, which hampers TR activity. Another site, known as the Z-site, located within the trypanothione cavity, has not yet been explored for inhibition.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Valentina Noemi Madia, Davide Ialongo, Elisa Patacchini, Cecile Exertier, Lorenzo Antonelli, Gianni Colotti, Antonella Messore, Valeria Tudino, Francesco Saccoliti, Luigi Scipione, Andrea Ilari, Roberta Costi, Roberto Di Santo
Summary: This research focused on the design and synthesis of new compounds structurally related to compound 1, and evaluated their inhibition activity on trypanothione reductase (TR) from Leishmania infantum. The results showed that compounds 2a and 2b were the most potent inhibitors, suggesting the potential of an additional aromatic ring for enzymatic inhibition. Further studies are needed to optimize the activity of these compounds through structure-activity relationships.
Review
Biochemistry & Molecular Biology
Roberto Mattioli, Andrea Ilari, Beatrice Colotti, Luciana Mosca, Francesco Fazi, Gianni Colotti
Summary: Anthracyclines are important and effective treatments for cancer, but their use is complicated by severe side effects and toxicity, including cardiotoxicity. The mode of action of anthracyclines is complex, and their high toxicity may be due to multiple mechanisms. The development of resistance to anthracyclines is a major barrier, but recent studies have addressed this issue. This article provides an overview of anthracycline use in cancer therapy, discussing their mechanisms of action, toxicity, and chemoresistance, as well as approaches to improve their effectiveness, reduce toxicity, and overcome resistance.
MOLECULAR ASPECTS OF MEDICINE
(2023)