A5046836115- Ion channel regulation and function
- Neuroscience and Neuropharmacology Research
- Cardiac electrophysiology and arrhythmias
- Nicotinic Acetylcholine Receptors Study
- Crystallization and Solubility Studies
- RNA and protein synthesis mechanisms
- X-ray Diffraction in Crystallography
- Ion Transport and Channel Regulation
- Receptor Mechanisms and Signaling
- Chemical Synthesis and Analysis
- Analytical Chemistry and Sensors
- Advanced Chemical Sensor Technologies
- Calcium signaling and nucleotide metabolism
- Adenosine and Purinergic Signaling
- Erythrocyte Function and Pathophysiology
- Membrane-based Ion Separation Techniques
- Electrochemical Analysis and Applications
- Medicinal Plant Extracts Effects
- Neuroscience and Neural Engineering
- Connexins and lens biology
- Hearing, Cochlea, Tinnitus, Genetics
- Alkaloids: synthesis and pharmacology
- Neural dynamics and brain function
- Marine Toxins and Detection Methods
- Peptidase Inhibition and Analysis
The University of Sydney
2015-2025
University of Copenhagen
2018-2024
Familial Meniere's disease (FMD) is a rare polygenic disorder of the inner ear. Mutations in connexin gene family, which encodes gap junction proteins, can also cause hearing loss, but their role FMD largely unknown. We retrieved exome sequencing data from 94 individuals 70 (MD) families. Through burden analysis, we calculated enrichment variants (allele frequency < 0.05) connexins genes compared with reference population. The monomer and homomeric connexon structural models were predicted...
The sodium leak channel (NALCN) is essential for survival in mammals: NALCN mutations are life-threatening humans and knockout lethal mice. However, the basic functional pharmacological properties of have remained elusive. Here, we found that robust function heterologous systems requires co-expression UNC79, UNC80, FAM155A. resulting complex constitutively active conducts monovalent cations but blocked by physiological concentrations extracellular divalent cations. Our data support notion...
Extracts of the pepper plant kava (Piper methysticum) are effective in alleviating anxiety clinical trials. Despite long-standing therapeutic interest kava, molecular target(s) pharmacologically active constituents, kavalactones have not been established. γ-Aminobutyric acid type A receptors (GABAARs) assumed to be vivo target based on data from binding assays, but evidence support a direct interaction between and GABAARs is scarce equivocal. In this study, we characterised functional...
Manipulation of proteins by chemical modification is a powerful way to decipher their function. However, most ribosome-dependent and semi-synthetic methods have limitations in the number type modifications that can be introduced, especially live cells. Here, we present an approach incorporate single or multiple post-translational non-canonical amino acids into expressed eukaryotic We insert synthetic peptides GFP, NaV1.5 P2X2 receptors via tandem protein trans-splicing using two orthogonal...
The sodium (Na + ) leak channel (NALCN) is a member of the four-domain voltage-gated cation family that includes prototypical and calcium channels V s Ca s, respectively). Unlike Na which have four lateral fenestrations serve as routes for lipophilic compounds to enter central cavity modulate function, NALCN has bulky residues (W311, L588, M1145, Y1436) block these openings. Structural data suggest occluded underlie pharmacological resistance NALCN, but functional evidence lacking. To test...
Unlike classical voltage-gated sodium (NaV) channels, NaX has been characterized as a voltage-insensitive, tetrodotoxin-resistant, (Na+)-activated channel involved in regulating Na+ homeostasis. However, remains refractory to functional characterization traditional heterologous systems. Here, gain insight into its atypical physiology, we determine structures of the human complex with auxiliary β3-subunit. reveals structural alterations within selectivity filter, voltage sensor-like domains,...
2’-Methoxy-6-methylflavone (2’MeO6MF) is an anxiolytic flavonoid which has been shown to display GABAA receptor (GABAAR) β2/3-subunit selectivity, a pharmacological profile similar that of the general anaesthetic etomidate. Electrophysiological studies suggest full agonist action 2’MeO6MF at α2β3γ2L GABAARs may mediate flavonoid’s in vivo effects. However, we found variations relative efficacy (2’MeO6MF-elicited current responses normalised maximal GABA response) due presence mixed...
γ-aminobutyric acid type A receptors (GABAARs), the major inhibitory neurotransmitter in mammalian central nervous system, are arguably most challenging member of pentameric Cys-loop to study due their heteromeric structure. When two or more subunits expressed together heterologous systems, variable subunit type, ratio, and orientation can form, precluding accurate interpretation data from functional studies. Subunit concatenation is a technique that involves linking individual theory allows...
Abstract Familial Meniere Disease (FMD) is a rare polygenic disorder of the inner ear. Mutations in connexin gene family, which encodes gap junction proteins, can also cause hearing loss, but their role FMD largely unknown. Here, we found an enrichment missense variants GJD3 when comparing allelic frequencies (N=94) with Spanish reference population (OR=3.9[1.92-7.91], FDR=2.36E-03). In sequence, identified haplotype (TGAGT) composed two missense, synonymous, and one downstream variants....
Abstract Halogenated analogues of the neurotoxic alkaloid muscimol were prepared with fluorine, iodine or trifluoromethyl at 4 position isoxazole ring system. These compounds investigated as agonists for GABA A receptors. Only C‐4 fluorine‐containing analogue proved to be an active compound in these assays. The fluoro was less than muscimol, however it showed differential activity between synaptic (α 1 β 2 γ ) and extrasynaptic γ) receptors, having a similar potency neurotransmitter receptor.
Abstract The sodium (Na + ) leak channel (NALCN) is a member of the four-domain voltage-gated cation family that includes prototypical and calcium channels V s Ca s, respectively). Unlike Na which have four lateral fenestrations serve as routes for lipophilic compounds to enter central cavity modulate function, NALCN has bulky residues (W311, L588, M1145 Y1436) block these openings. Structural data suggest oc-cluded underlie pharmacological resistance compounds, but functional evidence...