A5081370895- Connexins and lens biology
- Yersinia bacterium, plague, ectoparasites research
- Ion Transport and Channel Regulation
- Nicotinic Acetylcholine Receptors Study
- Ion channel regulation and function
- Hereditary Neurological Disorders
- Ion Channels and Receptors
- ATP Synthase and ATPases Research
- Mitochondrial Function and Pathology
- Healthcare and Venom Research
- Bacillus and Francisella bacterial research
Paul Scherrer Institute
2023-2024
ETH Zurich
2023
University of Lausanne
2018-2022
In myelinating Schwann cells, connection between myelin layers is mediated by gap junction channels (GJCs) formed docked connexin 32 (Cx32) hemichannels (HCs). Mutations in Cx32 cause the X-linked Charcot-Marie-Tooth disease (CMT1X), a degenerative neuropathy without cure. A molecular link dysfunction and CMT1X pathogenesis still missing. Here, we describe high-resolution cryo-electron microscopy (cryo-EM) structures of GJC HC, along with two CMT1X-linked mutants, W3S R22G. While wild-type...
Acid-sensing ion channels (ASICs) are neuronal Na+-permeable that activated by extracellular acidification and involved in fear sensing, learning, neurodegeneration after ischemia, pain sensation. We have recently found the human ASIC1a (hASIC1a) wild type (WT) clone which has been used many laboratories recombinant expression studies contains a point mutation occurs with very low frequency humans. Here, we compared function of WT this rare variant, highly conserved residue Gly212 is...
Acid-sensing ion channels (ASICs) are neuronal Na+-selective that open in response to extracellular acidification. They involved pain, fear, learning, and neurodegeneration after ischemic stroke. 2-Guanidine-4-methylquinazoline (GMQ) was recently discovered as the first nonproton activator of ASIC3. GMQ is interest a gating modifier pore blocker ASICs. It has however low potency, exerts opposite effects on ASIC1a To further explore molecular mechanisms action, we have used guanidinium moiety...
Abstract Connexin gap junction channels and hemichannels play important roles in intercellular communication signaling. Some of connexin isoforms are associated with diseases, including hereditary neuropathies, heart disease cancer. Although small molecule inhibitors connexins show promise as therapeutic agents, the molecular mechanisms channel inhibition unknown. Here, we report cryo-EM structure connexin-36 (Cx36) bound to an anti-malarial drug mefloquine at 2.1 Å resolution. Six binding...
Abstract Gap junction intercellular communication (GJIC) between two adjacent cells involves direct exchange of cytosolic ions and small molecules via connexin gap channels (GJCs). Connexin GJCs have emerged as drug targets, with molecule inhibitors considered a viable therapeutic strategy in several diseases. The molecular mechanisms GJC inhibition by known remain unknown, preventing the development more potent connexin-specific therapeutics. Here we show that inhibitors, mefloquine (MFQ)...
Gap junction intercellular communication (GJIC) between two adjacent cells involves direct exchange of cytosolic ions and small molecules via connexin gap channels (GJCs). Connexin GJCs have emerged as drug targets, with molecule inhibitors considered a viable therapeutic strategy in several diseases. The molecular mechanisms GJC inhibition by known remain unknown, preventing the development more potent connexin-specific therapeutics. Here we show that inhibitors, mefloquine (MFQ)...
Abstract In myelinating Schwann cells, communication between myelin layers is mediated by gap junction channels (GJC) formed docked connexin 32 hemichannels (HCs). Mutations in Cx32 cause the X-linked Charcot–Marie–Tooth disease (CMT1X), a degenerative neuropathy with no cure. A molecular link dysfunction and CMT1X pathogenesis still missing. Here, we describe high resolution cryo-EM structures of GJC HC, along two CMT1X-linked mutants, W3S R22G. While wild-type mutant GJCs are virtually...
Acid-sensing ion channels (ASICs) are neuronal, proton-gated, Na + -selective channels. They involved in various physiological and pathological processes such as neurodegeneration after stroke, pain sensation, fear behavior learning. To obtain information on the activation mechanism of ASIC1a, we attempted this study to impose distance constraints between paired residues different channel domains by using cross-linkers reacting with engineered Cys residues, measured how affected function....