A5024993436- Ion channel regulation and function
- Neuroscience and Neuropharmacology Research
- Nicotinic Acetylcholine Receptors Study
- Cellular transport and secretion
- Lipid Membrane Structure and Behavior
- Receptor Mechanisms and Signaling
- Neuroscience and Neural Engineering
- Pain Mechanisms and Treatments
- Ion Transport and Channel Regulation
- Neuropeptides and Animal Physiology
- Cardiac electrophysiology and arrhythmias
- Trace Elements in Health
- Microtubule and mitosis dynamics
- Academic Writing and Publishing
- Ubiquitin and proteasome pathways
- Venomous Animal Envenomation and Studies
- Cancer, Stress, Anesthesia, and Immune Response
- Vagus Nerve Stimulation Research
- Erythrocyte Function and Pathophysiology
- Lysosomal Storage Disorders Research
- Prion Diseases and Protein Misfolding
- Electromagnetic Fields and Biological Effects
- Coenzyme Q10 studies and effects
- Graphene and Nanomaterials Applications
- Sphingolipid Metabolism and Signaling
University College London
2012-2022
California Institute of Technology
2016
University of Würzburg
2006-2008
University of Tübingen
2006
Neuropathic pain results from damage to the peripheral sensory nervous system, which may have a number of causes. The calcium channel subunit alpha(2)delta-1 is upregulated in dorsal root ganglion (DRG) neurons several animal models neuropathic pain, and this causally related onset allodynia, non-noxious stimulus becomes painful. therapeutic drugs gabapentin pregabalin (PGB), are both alpha(2)delta ligands, antiallodynic effects, but their mechanism action has remained elusive. To...
Voltage-gated calcium channels are thought to exist in the plasma membrane as heteromeric proteins, which α1 subunit is associated with two auxiliary subunits, intracellular β and α 2 δ subunit; both of these subunits influence trafficking properties Ca V 1 channels. The have been described type I transmembrane because they an N-terminal signal peptide a C-terminal hydrophobic potentially region. However, very short cytoplasmic domains, we hypothesized that proteins might be through...
Significance The auxiliary α 2 δ-1 subunits of voltage-gated calcium (Ca V ) channels are important therapeutic targets, representing the receptor for gabapentinoid drugs in neuropathic pain therapy. It is therefore to understand their function. Because δ augment currents, it believed that they increase cell-surface expression these channels. Here, using exofacially tagged Ca 2.2 constructs, we now show this be case. However, recent proteomic analysis found associated only loosely and...
Voltage-gated calcium (CaV) channels form three subfamilies (CaV1-3). The CaV1 and CaV2 are heteromeric, consisting of an α1 pore-forming subunit, associated with auxiliary CaVβ α2δ subunits. subunits encoded in mammals by four genes, CACNA2D1-4. They play important roles trafficking function the CaV channel complexes. Here we report biallelic variants CACNA2D1, encoding α2δ-1 protein, two unrelated individuals showing a developmental epileptic encephalopathy. Patient 1 has homozygous...
The auxiliary α2δ subunits of voltage-gated calcium channels are extracellular membrane-associated proteins, which post-translationally cleaved into disulfide-linked polypeptides α2 and δ. We now show, using constructs containing artificial cleavage sites, that this processing is an essential step permitting voltage-dependent activation plasma membrane N-type (CaV2.2) channels. Indeed, uncleaved inhibits native currents in mammalian neurons. By inducing acute cell-surface proteolytic α2δ,...
Voltage-gated calcium channel auxiliary α2δ subunits are important for trafficking and function. Here, we compare the effects of α2δ-1 an α2δ-like protein called Cachd1 on neuronal N-type (CaV2.2) channels, which in neurotransmission. Previous structural studies show VWA domain interacting with first loop CaV1.1 domain-I via its metal ion-dependent adhesion site (MIDAS) motif additional Cache interactions. has a disrupted MIDAS motif. However, increases CaV2.2 currents substantially...
Abstract Voltage-gated Ca 2+ (Ca V ) channels consist of a pore-forming α1 subunit, which determines the main functional and pharmacological attributes channel. The 1 2 are associated with auxiliary β- α δ-subunits. molecular mechanisms involved in δ subunit trafficking, effect subunits on trafficking calcium channel complexes remain poorly understood. Here we show that δ-1 is ligand for Low Density Lipoprotein (LDL) Receptor-related Protein-1 (LRP1), multifunctional receptor mediates...
Abstract The α 2 δ proteins are auxiliary subunits of voltage-gated calcium channels and influence their trafficking biophysical properties. ligand gabapentin interacts with δ-1 inhibits channel trafficking. However, -1 has also been proposed to play a synaptogenic role, independent function. In this regard, was identified as thrombospondins, the interaction involving thrombospondin domain von-Willebrand-factor domain. Co-immunoprecipitation between thrombospondin-2 prevented by gabapentin....
Auxiliary α2δ subunits are important proteins for trafficking of voltage-gated calcium channels (CaV) at the active zones synapses. We have previously shown that post-translational proteolytic cleavage is essential their modulatory effects on N-type (CaV2.2) (Kadurin et al., 2016). extend these results here by showing probability presynaptic vesicular release reduced when an uncleaved expressed in rat neurons and this inhibitory effect reversed restored. also show asynchronous influenced...
There are four genes for acid-sensing ion channels (ASICs) in the genome of mammalian species. Whereas ASIC1 to ASIC3 form functional H+-gated Na+ channels, ASIC4 is not gated by H+, and its function unknown. Zebrafish has two paralogs: zASIC4.1 zASIC4.2. extracellular zASIC4.2 not. This differential response H+ makes zASIC4 paralogs a good model study properties this channel. In study, we found that surface expression homomeric higher than zASIC4.1. Surface was much increased formation...
Voltage-gated calcium channels are exquisitely Ca2+ selective, conferred primarily by four conserved pore-loop glutamate residues contributing to the selectivity filter. There has been little previous work directly measuring whether trafficking of requires their ability bind in filter or conduct Ca2+. Here, we examine neuronal CaV2.1 and 2.2 with mutations find reduced cell surface lines. Furthermore, hippocampal neurons, there is somatic plasma membrane, into neurites, presynaptic...
ASICs (acid-sensing ion channels) are H(+)-gated Na(+) channels with a widespread expression pattern in the central and peripheral nervous system. have simple topology two transmembrane domains, cytoplasmic termini large ectodomain between domains; this has been confirmed by crystal structure of chicken ASIC1. ASIC1a ASIC1b variants encoded asic1 gene. The variable part protein includes N-terminus, first domain approximately third ectodomain. Both contain consensus sequences for N-linked...
Stomatin is an integral membrane protein which widely expressed in many cell types. It accepted that stomatin has a unique hairpin-loop topology: it anchored to the with N-terminal hydrophobic domain and N- C-termini are cytoplasmically localized. prototype for family of related proteins, containing among others MEC-2 (mechanosensory 2) from Caenorhabditis elegans, SLP (stomatin-like protein)-3 podocin, all interact ion channels regulate their activity. Members partly localize DRMs...
It has been shown recently that PrP (prion protein) and the calcium channel auxiliary α2δ subunits interact in neurons expression systems [Senatore, Colleoni, Verderio, Restelli, Morini, Condliffe, Bertani, Mantovani, Canovi, Micotti, Forloni, Dolphin, Matteoli, Gobbi Chiesa (2012) Neuron 74, 300-313]. In present study we examined whether there was an effect of on currents. We have when is co-expressed with channels formed from CaV2.1/β α2δ-1 or α2δ-2, a consistent decrease current density....
Abstract The auxiliary α2δ subunits of voltage-gated calcium (CaV) channels are key to augmenting expression and function CaV1 CaV2 channels, also important drug targets in several therapeutic areas, including neuropathic pain. proteins translated as preproteins encoding both α2 δ, post-translationally proteolyzed into δ subunits, which remain associated a complex. In this study, we have identified ADAM17 protease involved proteolytic processing pro-α2δ-1 α2δ-3 subunits. We provide three...