Géza Berecki

Florey Institute of Neuroscience and Mental Health

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Steven Petrou

Florey Institute of Neuroscience and Mental Health

David J. Adams

University of Wollongong

Antoni C.G. van Ginneken

University of Amsterdam

Arie O. Verkerk

University of Amsterdam

David J. Craik

University of Queensland

Richard J. Clark

Next Energy Technologies (United States)

Hester M. den Ruijter

Utrecht University

Bert van Duijn

Leiden University

Christopher A. Reid

Vital Therapies (United States)

Ronald Wilders

University of Amsterdam

Cooperative Institutions

University of Melbourne

University of Queensland

Florey Institute of Neuroscience and Mental Health

Academic Medical Center

University of Amsterdam

Royal Children's Hospital

Austin Health

RMIT University

University Medical Center Utrecht

Monash University

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Een functionele studie naar aangeboren gebrekkige natriumkanalen door middel van dynamic action potential clamp

Géza Berecki Antoni C.G. van Ginneken

Clamp

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Citations (0)

Corrigendum to “Biophysical analysis of an HCN1 epilepsy variant suggests a critical role for S5 helix Met-305 in voltage sensor to pore domain coupling” [Prog. Biophys. Mol. Biol. 166 (2021) 156–172]

Progress in Biophysics and Molecular Biology (2022)

Andrew Hung Ian C. Forster Chaseley E. McKenzie Géza Berecki Steven Petrou

Helix (gastropod)

10.1016/j.pbiomolbio.2022.05.003

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Effects of arginine 10 to lysine substitution on ω‐conotoxin CVIE and CVIF block of Ca_v2.2 channels

British Journal of Pharmacology (2014)

Géza Berecki Norelle L. Daly Yen‐Hua Huang Simone Vink David J. Craik

ω-Conotoxins CVIE and CVIF (CVIE&F) selectively inhibit Cav2.2 channels and are lead molecules in the development of novel analgesics. At physiological membrane potentials, CVIE&F block of Cav2.2 channels is weakly reversible. To improve reversibility, we designed and synthesized arginine CVIE&F analogues in which arginine was substituted for lysine at position 10 ([R10K]CVIE&F), and investigated their serum stability and pharmacological actions on voltage-gated calcium channels (VGCCs).Changes in peptide structure due to R10K substitution were assessed by NMR. Peptide stability in human serum was analysed by reversed-phase HPLC and MS over a 24 h period. Two-electrode voltage-clamp and whole-cell patch clamp techniques were used to study [R10K]CVIE&F effects on VGCC currents in Xenopus oocytes and rat dorsal root ganglion neurons respectively.R10K substitution did not change the conserved ω-conotoxin backbone conformations of CVIE&F nor the ω-conotoxin selectivity for recombinant or native Cav2.2 channels, although the inhibitory potency of [R10K]CVIF was better than that of CVIF. At -80 mV, the R10K chemical modification significantly affected ω-conotoxin-channel interaction, resulting in faster onset kinetics than those of CVIE&F. Heterologous and native Cav2.2 channels recovered better from [R10K]CVIE&F block than CVIE&F. In human serum, the ω-conotoxin half-lives were 6-10 h. CVIE&F and [R10K]CVIE&F were more stable than CVID.R10K substitution in CVIE&F significantly alters the kinetics of ω-conotoxin action and improves reversibility without diminishing conotoxin potency and specificity for the Cav2.2 channel and without diminishing the serum stability. These results may help generate ω-conotoxins with optimized kinetic profiles for target binding.

Conotoxin

10.1111/bph.12686

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Citations (6)

Structure–Activity Studies of Cysteine‐Rich α‐Conotoxins that Inhibit High‐Voltage‐Activated Calcium Channels via GABA_B Receptor Activation Reveal a Minimal Functional Motif

Angewandte Chemie International Edition (2016)

Bodil B. Carstens Géza Berecki James T. Daniel Han Siean Lee Kathryn Jackson

Abstract α‐Conotoxins are disulfide‐rich peptides that target nicotinic acetylcholine receptors. Recently we identified several α‐conotoxins that also modulate voltage‐gated calcium channels by acting as G protein‐coupled GABA B receptor (GABA B R) agonists. These α‐conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the diversity of α‐conotoxins that act through this mechanism, we synthesized and characterized a set of peptides with homology to α‐conotoxins known to inhibit high voltage‐activated calcium channels via GABA B R activation. Remarkably, all disulfide isomers of the active α‐conotoxins Pu1.2 and Pn1.2, and the previously studied Vc1.1 showed similar levels of biological activity. Structure determination by NMR spectroscopy helped us identify a simplified biologically active eight residue peptide motif containing a single disulfide bond that is an excellent lead molecule for developing a new generation of analgesic peptide drugs.

Conotoxin

10.1002/anie.201600297

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Citations (50)

HERG Channel (Dys)function Revealed by Dynamic Action Potential Clamp Technique

Biophysical Journal (2004)

Géza Berecki Jan G. Zegers Arie O. Verkerk Zahurul A. Bhuiyan Berend de Jonge

hERG

Short QT syndrome

Cardiac action potential

Ventricular action potential

HEK 293 cells

10.1529/biophysj.104.047290

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Citations (93)

The presence and subcellular localization of caspase 3‐like proteinases in plant cells

FEBS Letters (2000)

Henrie A. A. J. Korthout Géza Berecki W. J. Bruin Bert van Duijn Mei Wang

Caspases play a very important role in initiating and executing apoptotic processes in animal cells. In this study we show that plant mitochondria were able to initiate the activation of caspase 3 in a Xenopus cell free system. Caspase 3‐like activity was found to be present in plant cells and could only be inhibited by the specific caspase 3 inhibitor N ‐acetyl‐Asp‐Glu‐Val‐Asp‐fluoromethylketone (Ac‐DEVD‐fmk) and not by cysteine protease inhibitors. By micro‐injection of the caspase 3 substrate in living Chara cells we showed that caspase 3‐like activity was mainly present in the cytosol rather than in the vacuole. This is the first time that in vivo caspase 3‐like activity has been demonstrated in plants.

Cysteine protease

Caspase 2

Caspase-9

Plant cell

NLRP1

10.1016/s0014-5793(00)01643-4

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Citations (124)

Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy

Proceedings of the National Academy of Sciences (2018)

Géza Berecki Katherine B. Howell Yadeesha Hasalanka Deerasooriya Maria Roberta Cilio Megan Oliva

Significance SCN2A , encoding the voltage-gated sodium channel Na v 1.2, has emerged as a major gene implicated in neonatal-, infantile-, and even childhood-onset epilepsies. Many of these epilepsies are also associated with cognitive and behavioral impairments that range in type and severity. The biophysical, neurophysiological, and clinical impacts of SCN2A mutations are poorly understood. Here, we use clinical evaluation and biophysical analyses to explore the mechanisms underpinning distinctive phenotypes produced by SCN2A variants associated with mild familial or severe de novo forms of epilepsy. We show that dynamic clamp analysis provides clear benefits over conventional voltage clamp for a rapid and definitive prediction of neuron-scale phenotypic consequences, and is well positioned to impact diagnosis and drug discovery in genetic epilepsy.

10.1073/pnas.1800077115

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Citations (78)

A Novel Antisense Oligonucleotide for the Treatment of Early Onset SCN2A Developmental and Epileptic Encephalopathy: A First-in-Patient Report in a Preterm Infant with Refractory Status Epilepticus

Neuropediatrics (2024)

Matias Wagner Claudia Nußbaum Géza Berecki Andreas W. Flemmer S. Frizzo

Background/Purpose: Early-onset SCN2A developmental and epileptic encephalopathy (SCN2A-DEE) is a rare, severe, and fatal pediatric disorder characterized by frequent, epileptic seizures, typically beginning within days of birth, and often difficult to control with standard-of-care antiseizure medications (ASMs). Comorbidities are extensive and devastating, including profound global developmental impairment and frequent hospitalization.

Refractory (planetary science)

10.1055/s-0044-1791879

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Fish oil reduces the number of calcium after-transients and delayed afterdepolarizations in isolated myocytes from rabbits with heart failure

Circulation (2005)

Hester M. den Ruijter Géza Berecki Peter L. Zock

Afterdepolarization

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Citations (5)

A New Target for the Alpha-Conotoxins: The GABAB Receptor