Review
Physiology
Mauricio A. Retamal, Guillermo A. Altenberg
Summary: Connexins are proteins that can form hemichannels and gap junction channels. In the lens, connexins play important roles in metabolic cooperation between cells and their modulation is involved in cataract formation. This review focuses on the functions of Cx46 hemichannels and gap junction channels and their posttranslational modifications.
FRONTIERS IN PHYSIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Alice McDouall, Kelly Q. Zhou, Laura Bennet, Colin R. Green, Alistair J. Gunn, Joanne O. Davidson
Summary: Perinatal brain injury, caused by hypoxia-ischemia and/or infection/inflammation, is a major cause of disability. Despite the effectiveness of therapeutic hypothermia, additional interventions are needed as nearly half of the infants still have adverse outcomes. Recent studies have shown that brain injury spreads over time from the initial site to previously unaffected regions, partly due to the opening of connexin hemichannels and pannexin channels. Blockade of these channels has demonstrated neuroprotective effects in animal models, suggesting their potential as targeted interventions in combination or separate from therapeutic hypothermia.
Review
Biochemistry & Molecular Biology
Raf Van Campenhout, Ana Rita Gomes, Timo W. M. De Groof, Serge Muyldermans, Nick Devoogdt, Mathieu Vinken
Summary: Gap junctions and connexin hemichannels play different roles in intercellular and extracellular communication, with the former maintaining homeostasis and the latter being associated with the onset and spread of disease by mediating messenger transport that fuels inflammation and cell death in various diseases. The present review discusses the mechanisms involved in the activation of connexin hemichannels during pathology.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cardiac & Cardiovascular Systems
Alessio Lissoni, Paco Hulpiau, Tania Martins-Marques, Nan Wang, Geert Bultynck, Rainer Schulz, Katja Witschas, Henrique Girao, Maarten De Smet, Luc Leybaert
Summary: The research revealed that the activation of ryanodine receptors (RyRs) triggers unitary currents with a single-channel conductance of around 220 pS, which are significantly reduced by knocking down connexin 43 (Cx43). The study also showed that both RyR activation and intracellular Ca2+ elevation are necessary for the opening of Cx43 hemichannels.
CARDIOVASCULAR RESEARCH
(2021)
Article
Neurosciences
Alice McDouall, Guido Wassink, Sumudu Ranasinghe, Kelly Q. Zhou, Rashika N. Karunasinghe, Justin M. Dean, Joanne O. Davidson
Summary: This study found that blocking connexin 43 hemichannels can attenuate brain injury and promote neurodevelopment in infants with mild hypoxic-ischemic encephalopathy, without causing hypothermia.
EXPERIMENTAL NEUROLOGY
(2024)
Article
Biology
Chao Qi, Silvia Acosta Gutierrez, Pia Lavriha, Alaa Othman, Diego Lopez-Pigozzi, Erva Bayraktar, Dina Schuster, Paola Picotti, Nicola Zamboni, Mario Bortolozzi, Francesco Luigi Gervasio, Volodymyr M. Korkhov
Summary: In this study, the structure of a human Cx43 GJC was determined using cryo-EM and single particle analysis. The pore region of Cx43 GJC was found to have lipid-like densities, and a previously undescribed conformation was discovered on the cytosolic side of the pore. Molecular dynamics simulations revealed the channel properties of Cx43. The captured states of Cx43 were consistent with a closed state.
Article
Biochemistry & Molecular Biology
Paul E. Squires, Gareth W. Price, Ulrik Mouritzen, Joe A. Potter, Bethany M. Williams, Claire E. Hills
Summary: Danegaptide has been shown to block hemichannel-mediated changes in protein expression and function in tubular epithelial kidney cells, protecting against tubular injury. It also inhibits TGF beta 1-induced changes in the expression and secretion of key adipokines, cytokines, chemokines, growth factors, and interleukins, indicating its potential in the future treatment of CKD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Pharmacology & Pharmacy
Di Yang, Mengyuan Chen, Sijia Yang, Furong Deng, Xinbiao Guo
Summary: Connexin hemichannels and pannexin channels are transmembrane channels that facilitate the exchange of ions and molecules between intra- and extracellular compartments. However, their excessive opening can disrupt cell homeostasis and function due to the permeation of toxic substances and essential metabolites. This review explores the activation of these channels by external stimuli and their involvement in toxicological pathways, including inflammation and oxidative damage.
Article
Biology
Ji Xu, Bruce J. Nicholson
Summary: This study investigated the characteristics of Cx30 hemichannels using heterologous expression systems. It was found that Cx30 hemichannels are sensitive to voltage and extracellular Ca2+ and show minimal selectivity for small ions but increased permeability for larger anions. Comparison with Cx26 gap junctions in the cochlea revealed differences in ATP permeability, indicating distinct physiological functions of Cx30 and Cx26 in energy distribution.
Article
Biochemistry & Molecular Biology
Joe A. Potter, Gareth W. Price, Chelsy L. Cliff, Colin R. Green, Paul E. Squires, Claire E. Hills
Summary: Chronic Kidney Disease is associated with inflammation and fibrosis, in this study, collagen I is shown to regulate cell function through connexin-43 hemichannel-mediated ATP release, emphasizing its role in renal disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biology
Bo Peng, Chengping Xu, Shuaiwei Wang, Yijie Zhang, Wei Li
Summary: This article provides an updated view of the role of connexin hemichannels in inflammatory diseases, as well as the progress in developing selective blockers for these channels. Opening of connexin hemichannels promotes inflammation, while blockade of these channels leads to reduced inflammation, tissue injury and improved organ function.
Article
Biochemistry & Molecular Biology
Felipe Villanelo, Jorge Carrasco, Joaquin Jensen-Flores, Jose Antonio Garate, Tomas Perez-Acle
Summary: Connexin hemichannels facilitate the exchange of molecules such as ions, water, and ATP between eukaryotic cells and their extracellular space. Regulation of these channels by extracellular Ca2+ concentration is known to influence their open or closed state, but the exact mechanisms involved are still not fully understood. Studies using molecular dynamics simulations suggest that pore stretching at the center of the connexin hemichannels may be the key factor in channel blocking, rather than the addition of positive charge density inside the channel.
Review
Pharmacology & Pharmacy
Motohiro Okada
Summary: ADSHE, caused by CHNRA4 mutation, is a genetic epilepsy where mutant molecules play important roles in epileptogenesis/ictogenesis. Research involving experimental models has revealed the pathomechanisms of ADSHE, proposing a hypothesis associated with tripartite synaptic transmission induced by mutant ACh receptors.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Olivia E. Crouthamel, Leping Li, Michael T. Dilluvio, Thomas W. White
Summary: Mutations in the GJA1 gene encoding connexin43 (Cx43) have been linked to various rare genetic disorders, including those affecting the skin. This study investigated the functional consequences of a specific Cx43 mutation (Cx43-G38E) associated with a novel human phenotype. The research showed that the mutation increased the activity of hemichannels, suggesting a potential role in skin and skeletal disorders caused by Cx43 mutations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Neurosciences
Sarbjit Nijjar, Daniel Maddison, Louise Meigh, Elizabeth de Wolf, Thomas Rodgers, Martin J. Cann, Nicholas Dale
Summary: A moderate increase in PCO2 (55 mmHg) can close Cx26 gap junctions independently of changes in pH, relying on specific residues and a carbamylation reaction. Pathological mutations of Cx26 can abolish this CO2-dependent closing effect, which is mediated through changes in protein entropy state. The action of CO2 on Cx26 gap junctions is different from its effect on hemichannels, with opposing actions dependent on the same residues and presumed carbamylation reaction.
JOURNAL OF PHYSIOLOGY-LONDON
(2021)
Review
Physiology
Morten S. Nielsen, Chantal J. M. van Opbergen, Toon A. B. van Veen, Mario Delmar
Summary: The intercalated disc (ID) is a specialized structure that connects cardiomyocytes via mechanical and electrical junctions. Recent studies have revealed the complex nanostructure and molecular composition of the ID, highlighting the fact that it is not just a simple cell-to-cell coupling junction but rather an interacting molecular complex. Understanding the physiological implications of the ID architecture and the local intermolecular interactions is crucial for understanding normal cardiac conduction and the pathophysiology of arrhythmias.
PHYSIOLOGICAL REVIEWS
(2023)
Article
Neurosciences
Nina Rostgaard, Markus Harboe Olsen, Maud Ottenheijm, Lylia Drici, Anja Hviid Simonsen, Peter Plomgaard, Hanne Gredal, Helle Harding Poulsen, Henrik Zetterberg, Kaj Blennow, Steen Gregers Hasselbalch, Nanna MacAulay, Marianne Juhler
Summary: This study aimed to compare the molecular composition of cerebrospinal fluid (CSF) obtained from the ventricular and the lumbar compartments and evaluate the feasibility of using lumbar CSF as a proxy for ventricular CSF. Results showed differences in protein composition and distribution of clinically employed biomarkers between the two compartments. However, for certain proteins and biomarkers, lumbar CSF can be reliably used as a proxy for ventricular CSF if a lumbar/cranial index has been established. It is important to verify the compartmental preference before extrapolating from lumbar CSF to ventricular fluid.
FLUIDS AND BARRIERS OF THE CNS
(2023)
Article
Neurosciences
Pooya Razzaghi Khamesi, Vasileios Charitatos, Eva K. K. Heerfordt, Nanna MacAulay, Vartan Kurtcuoglu
Summary: A computational model was developed to examine the role of the standing osmotic gradient mechanism in cerebrospinal fluid (CSF) production by the ventricular choroid plexus (ChP). The model suggests that the standing osmotic gradients have minimal effect on CSF production and are unlikely to be the main drivers.
FLUIDS AND BARRIERS OF THE CNS
(2023)
Article
Neurosciences
Jonathan H. Wardman, Mette N. Jensen, Soren N. Andreassen, Bjarne Styrishave, Jens E. Wilhjelm, Alexandra J. Sinclair, Nanna MacAulay
Summary: Idiopathic intracranial hypertension (IIH) is characterized by increased intracranial pressure, impaired vision, and headache. This study investigated the role of obesity and hormonal perturbations in IIH pathophysiology using rat models. The results suggest that obesity-induced androgen dysregulation may contribute to the disease mechanism of IIH.
FLUIDS AND BARRIERS OF THE CNS
(2023)
Article
Neurosciences
Annette Buur Steffensen, Beatriche Louise Edelbo, Dagne Barbuskaite, Soren Norge Andreassen, Markus Harboe Olsen, Kirsten Moller, Nanna MacAulay
Summary: Maintaining intracranial pressure (ICP) within the physiological range is crucial for proper brain function. Fluctuations in ICP during the light-dark phase cycle may complicate diagnosis and treatment choice for patients with pressure-related disorders. These fluctuations are likely caused by circadian or sleep-wake cycle-mediated modulation of cerebrospinal fluid (CSF) flow dynamics, which may also play a role in diurnal regulation of brain waste clearance.
FLUIDS AND BARRIERS OF THE CNS
(2023)
Article
Biochemistry & Molecular Biology
Nina Rostgaard, Markus Harboe Olsen, Tenna Capion, Nanna MacAulay, Marianne Juhler
Summary: This study aimed to identify inflammatory biomarkers in cerebrospinal fluid (CSF) that can predict the development of post-hemorrhagic hydrocephalus (PHH) and shunt-dependency, as well as functional outcome in patients with subarachnoid hemorrhage (SAH). Proximity extension assay (PEA) was used to analyze CSF samples from 31 SAH patients, and 7 markers were identified as predictors of shunt dependency and 4 markers as predictors of functional outcome. These inflammatory biomarkers hold potential as predictive tools in the clinic.
Article
Cardiac & Cardiovascular Systems
Olga M. Rusiecka, Filippo Molica, Morten S. Nielsen, Axel Tollance, Sandrine Morel, Maud Frieden, Marc Chanson, Kerstin Boengler, Brenda R. Kwak
Summary: This study found that deletion of the Pannexin1 (Panx1) gene in cardiac endothelial cells can alleviate cardiac ischaemia/reperfusion (I/R) injury and improve left ventricular function recovery. This cardioprotective effect seems to be mediated through its influence on cardiac mitochondria rather than reducing the inflammatory response. Therefore, Panx1 may represent a new target for controlling cardiac reperfusion damage.
CARDIOVASCULAR RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Sara Diana Lolansen, Nina Rostgaard, Tenna Capion, Nicolas H. Norager, Markus Harboe Olsen, Marianne Juhler, Tiit Illimar Mathiesen, Nanna MacAulay
Summary: The molecular mechanisms underlying the development of posthemorrhagic hydrocephalus (PHH) remain unclear, but elevated cerebrospinal fluid (CSF) osmolality is not the cause of PHH. The pathological CSF accumulation observed in these patients is instead attributed to other pathological alterations associated with the abnormal presence of blood within the CSF compartments following subarachnoid hemorrhage (SAH).
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Neurosciences
Sara Diana Lolansen, Dagne Barbuskaite, Fenghui Ye, Jianming Xiang, Richard F. Keep, Nanna MacAulay
Summary: This study elucidated the molecular mechanisms underlying the development of hydrocephalus in spontaneously hypertensive rats (SHRs), and found that it is not associated with elevated intracranial pressure (ICP) and does not require increased cerebrospinal fluid (CSF) secretion or inefficient CSF drainage. This type of hydrocephalus is not life-threatening and occurs due to unknown disturbances in CSF dynamics.
FLUIDS AND BARRIERS OF THE CNS
(2023)
Article
Biochemistry & Molecular Biology
Trine L. Toft-Bertelsen, Soren Norge Andreassen, Nina Rostgaard, Markus Harboe Olsen, Nicolas H. Norager, Tenna Capion, Marianne Juhler, Nanna Macaulay
Summary: The lipidomic signature of CSF in patients with subarachnoid hemorrhage suggests dysregulation of lipids and potential biomarkers for future treatment options.
Review
Clinical Neurology
Shai David Ben-Shoshan, Sara Diana Lolansen, Tiit Illimar Mathiesen, Nanna Macaulay
Summary: This systematic review aims to explore the molecular mechanisms underlying posthemorrhagic hydrocephalus (PHH) by evaluating existing literature on increased CSF secretion and impaired CSF absorption. The results suggest that the pathological accumulation of cerebrospinal fluid in PHH may arise from a combination of increased secretion and impaired absorption, which may manifest at different time scales following a hemorrhagic event.
ACTA NEUROCHIRURGICA
(2023)
Article
Multidisciplinary Sciences
Beatriche Louise Edelbo, Soren Norge Andreassen, Annette Buur Steffensen, Nanna Macaulay, Christian Metallo
Summary: The cerebrospinal fluid (CSF) provides mechanical protection for the brain and serves as a brain dispersion route for nutrients, hormones, and metabolic waste. CSF secretion rate is elevated in the dark phase and shows similarities in day-active humans and nocturnal rats, suggesting circadian regulation. Transcriptomic and metabolomic analysis reveals significant fluctuation in CSF metabolites and differential expression of choroid plexus genes between light and dark phases, indicating light-dark phase-mediated changes in rat choroid plexus and its surrounding CSF. These findings provide insights into the molecular pathways governing CSF dynamics and potential applications in pathology.
Article
Cell Biology
Nanna Macaulay, Trine L. Toft-Bertelsen
Summary: The choroid plexus is a crucial tissue in the brain that secretes cerebrospinal fluid and maintains electrolyte balance. It is regulated by various membrane transporters and plays a vital role in controlling potassium levels in the brain. This dual function of the choroid plexus is important for overall brain function.
Article
Clinical Neurology
Nina Rostgaard, Markus Harboe Olsen, Sara Diana Lolansen, Nicolas Hernandez Norager, Peter Plomgaard, Nanna Macaulay, Marianne Juhler
Summary: By using a proteomic approach, this study aimed to identify potential protein biomarkers in cerebrospinal fluid (CSF) that can differentiate between obstructive and communicating hydrocephalus, as well as predict surgical outcomes. The analysis identified several proteins with differential abundance in CSF from hydrocephalus patients compared to control subjects, and identified ten proteins that can predict response to surgery in obstructive hydrocephalus.
ACTA NEUROCHIRURGICA
(2023)
Meeting Abstract
Physiology
D. Barbuskaite, E. K. Oernbo, J. H. Wardman, T. L. Toft-Bertelsen, E. Conti, S. N. Andreassen, N. Gerkau, C. Rose, N. MacAulay