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Annette Dolphin

Alexandros H Kanellopoulos, Jennifer Koenig, Honglei Huang, Martina Pyrski, Queensta Millet, Stéphane Lolignier, Toru Morohashi, Samuel J Gossage, Maude Jay, John E Linley, Georgios Baskozos, Benedikt M Kessler, James J Cox, Annette C Dolphin, Frank Zufall, John N Wood, Jing Zhao
The voltage-gated sodium channel NaV 1.7 plays a critical role in pain pathways. We generated an epitope-tagged NaV 1.7 mouse that showed normal pain behaviours to identify channel-interacting proteins. Analysis of NaV 1.7 complexes affinity-purified under native conditions by mass spectrometry revealed 267 proteins associated with Nav1.7 in vivo The sodium channel β3 (Scn3b), rather than the β1 subunit, complexes with Nav1.7, and we demonstrate an interaction between collapsing-response mediator protein (Crmp2) and Nav1...
February 1, 2018: EMBO Journal
Jean Chemin, Valentina Taiakina, Arnaud Monteil, Michael Piazza, Wendy Guan, Robert F Stephens, Ashraf Kitmitto, Zhiping P Pang, Annette C Dolphin, Edward Perez-Reyes, Thorsten Dieckmann, Joseph Guy Guillemette, J David Spafford
Calcium (Cav 1 and Cav 2) and sodium channels possess homologous CaM-binding motifs, known as IQ motifs in their C termini, which associate with calmodulin (CaM), a universal calcium sensor. Cav 3 T-type channels, which serve as pacemakers of the mammalian brain and heart, lack a C-terminal IQ motif. We illustrate that T-type channels associate with CaM using co-immunoprecipitation experiments and single particle cryo-electron microscopy. We demonstrate that protostome invertebrate (LCav 3) and human Cav 3...
December 8, 2017: Journal of Biological Chemistry
Ivan Kadurin, Simon W Rothwell, Beatrice Lana, Manuela Nieto-Rostro, Annette C Dolphin
Voltage-gated Ca(2+) (CaV) channels consist of a pore-forming α1 subunit, which determines the main functional and pharmacological attributes of the channel. The CaV1 and CaV2 channels are associated with auxiliary β- and α2δ-subunits. The molecular mechanisms involved in α2δ subunit trafficking, and the effect of α2δ subunits on trafficking calcium channel complexes remain poorly understood. Here we show that α2δ-1 is a ligand for the Low Density Lipoprotein (LDL) Receptor-related Protein-1 (LRP1), a multifunctional receptor which mediates trafficking of cargoes...
March 3, 2017: Scientific Reports
Lilian Kisiswa, Clara Erice, Laurent Ferron, Sean Wyatt, Catarina Osório, Annette C Dolphin, Alun M Davies
Tumour necrosis factor receptor 1 (TNFR1)-activated TNFα reverse signalling, in which membrane-integrated TNFα functions as a receptor for TNFR1, enhances axon growth from developing sympathetic neurons and plays a crucial role in establishing sympathetic innervation. Here, we have investigated the link between TNFα reverse signalling and axon growth in cultured sympathetic neurons. TNFR1-activated TNFα reverse signalling promotes Ca2+ influx, and highly selective T-type Ca2+ channel inhibitors, but not pharmacological inhibitors of L-type, N-type and P/Q-type Ca2+ channels, prevented enhanced axon growth...
January 2017: Open Biology
Ivan Kadurin, Laurent Ferron, Simon W Rothwell, James O Meyer, Leon R Douglas, Claudia S Bauer, Beatrice Lana, Wojciech Margas, Orpheas Alexopoulos, Manuela Nieto-Rostro, Wendy S Pratt, Annette C Dolphin
The auxiliary α2 δ subunits of voltage-gated calcium channels are extracellular membrane-associated proteins, which are post-translationally cleaved into disulfide-linked polypeptides α2 and δ. We now show, using α2 δ constructs containing artificial cleavage sites, that this processing is an essential step permitting voltage-dependent activation of plasma membrane N-type (CaV 2.2) calcium channels. Indeed, uncleaved α2δ inhibits native calcium currents in mammalian neurons. By inducing acute cell-surface proteolytic cleavage of α2 δ, voltage-dependent activation of channels is promoted, independent from the trafficking role of α2 δ...
October 26, 2016: ELife
Angela Emilia Ricarda Gimmel, Katrin Baumgartner, Annette Liesegang
BACKGROUND: As fish eaters bottlenose dolphins (Tursiops truncatus) in human care need to receive daily vitamin supplementation, because whole thawed fish lacks certain vitamins. However, the exact concentration of supplementation has not been established and is a matter of discussion. To ensure adequate vitamin supplementation in pets, vitamin blood concentrations are measured. This is not a common practice in dolphins. The objective of the present study was to collect information about vitamin supplementation in bottlenose dolphins and on vitamin blood concentrations of healthy animals in European facilities...
September 5, 2016: BMC Veterinary Research
Karen M Page, Simon W Rothwell, Annette C Dolphin
CaVβ subunits interact with the voltage-gated calcium channel CaV2.2 on a site in the intracellular loop between domains I and II (the I-II loop). This interaction influences the biophysical properties of the channel and leads to an increase in its trafficking to the plasma membrane. We have shown previously that a mutant CaV2.2 channel that is unable to bind CaVβ subunits (CaV2.2 W391A) was rapidly degraded (Waithe, D., Ferron, L., Page, K. M., Chaggar, K., and Dolphin, A. C. (2011) J. Biol. Chem. 286, 9598-9611)...
September 23, 2016: Journal of Biological Chemistry
Wojciech Margas, Laurent Ferron, Manuela Nieto-Rostro, Arnold Schwartz, Annette C Dolphin
Gene deletion of the voltage-gated calcium channel auxiliary subunit α2δ-1 has been shown previously to have a cardiovascular phenotype, and a reduction in mechano- and cold sensitivity, coupled with delayed development of neuropathic allodynia. We have also previously shown that dorsal root ganglion (DRG) neuron calcium channel currents were significantly reduced in α2δ-1 knockout mice. To extend our findings in these sensory neurons, we have examined here the properties of action potentials (APs) in DRG neurons from α2δ-1 knockout mice in comparison to their wild-type (WT) littermates, in order to dissect how the calcium channels that are affected by α2δ-1 knockout are involved in setting the duration of individual APs and their firing frequency...
August 5, 2016: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
Annette C Dolphin
Voltage-gated calcium channels are essential players in many physiological processes in excitable cells. There are three main subdivisions of calcium channel, defined by the pore-forming α1 subunit, the CaV 1, CaV 2 and CaV 3 channels. For all the subtypes of voltage-gated calcium channel, their gating properties are key for the precise control of neurotransmitter release, muscle contraction and cell excitability, among many other processes. For the CaV 1 and CaV 2 channels, their ability to reach their required destinations in the cell membrane, their activation and the fine tuning of their biophysical properties are all dramatically influenced by the auxiliary subunits that associate with them...
October 1, 2016: Journal of Physiology
Shehrazade Dahimene, Karen M Page, Manuela Nieto-Rostro, Wendy S Pratt, Marianna D'Arco, Annette C Dolphin
Episodic ataxia 2 (EA2) is an autosomal dominant disorder caused by mutations in the gene CACNA1A that encodes the pore-forming CaV2.1 calcium channel subunit. The majority of EA2 mutations reported so far are nonsense or deletion/insertion mutations predicted to form truncated proteins. Heterologous expression of wild-type CaV2.1, together with truncated constructs that mimic EA2 mutants, significantly suppressed wild-type calcium channel function, indicating that the truncated protein produces a dominant-negative effect (Jouvenceau et al...
September 2016: Neurobiology of Disease
Beatrice Lana, Karen M Page, Ivan Kadurin, Shuxian Ho, Manuela Nieto-Rostro, Annette C Dolphin
The α2δ proteins are auxiliary subunits of voltage-gated calcium channels, and influence their trafficking and biophysical properties. The α2δ ligand gabapentin interacts with α2δ-1, and inhibits calcium channel trafficking. However, α2-1 has also been proposed to play a synaptogenic role, independent of calcium channel function. In this regard, α2δ-1 was identified as a ligand of thrombospondins, with the interaction involving the thrombospondin synaptogenic domain and the α2δ-1 von-Willebrand-factor domain...
April 14, 2016: Scientific Reports
Natsuko Macabuag, Annette C Dolphin
N-type voltage-gated calcium (Ca(V)2.2) channels are expressed in neurons and targeted to the plasma membrane of presynaptic terminals, facilitating neurotransmitter release. Here, we find that the adaptor protein complex-1 (AP-1) mediates trafficking of Ca(V)2.2 from the trans-Golgi network to the cell surface. Examination of splice variants of Ca(V)2.2, containing either exon 37a (selectively expressed in nociceptors) or 37b in the proximal C terminus, reveal that canonical AP-1 binding motifs, YxxΦ and [DE]xxxL[LI], present only in exon 37a, enhance intracellular trafficking of exon 37a-containing Ca(V)2...
October 28, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Samuel Heyes, Wendy S Pratt, Elliott Rees, Shehrazade Dahimene, Laurent Ferron, Michael J Owen, Annette C Dolphin
This review summarises genetic studies in which calcium channel genes have been connected to the spectrum of neuropsychiatric syndromes, from bipolar disorder and schizophrenia to autism spectrum disorders and intellectual impairment. Among many other genes, striking numbers of the calcium channel gene superfamily have been implicated in the aetiology of these diseases by various DNA analysis techniques. We will discuss how these relate to the known monogenic disorders associated with point mutations in calcium channels...
November 2015: Progress in Neurobiology
Gerald W Zamponi, Joerg Striessnig, Alexandra Koschak, Annette C Dolphin
Voltage-gated calcium channels are required for many key functions in the body. In this review, the different subtypes of voltage-gated calcium channels are described and their physiologic roles and pharmacology are outlined. We describe the current uses of drugs interacting with the different calcium channel subtypes and subunits, as well as specific areas in which there is strong potential for future drug development. Current therapeutic agents include drugs targeting L-type Ca(V)1.2 calcium channels, particularly 1,4-dihydropyridines, which are widely used in the treatment of hypertension...
October 2015: Pharmacological Reviews
Marianna D'Arco, Wojciech Margas, John S Cassidy, Annette C Dolphin
As auxiliary subunits of voltage-gated Ca(2+) channels, the α2δ proteins modulate membrane trafficking of the channels and their localization to specific presynaptic sites. Following nerve injury, upregulation of the α2δ-1 subunit in sensory dorsal root ganglion neurons contributes to the generation of chronic pain states; however, very little is known about the underlying molecular mechanisms. Here we show that the increased expression of α2δ-1 in rat sensory neurons leads to prolonged Ca(2+) responses evoked by membrane depolarization...
April 15, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
John S Cassidy, Laurent Ferron, Ivan Kadurin, Wendy S Pratt, Annette C Dolphin
CaV1 and CaV2 voltage-gated calcium channels are associated with β and α2δ accessory subunits. However, examination of cell surface-associated CaV2 channels has been hampered by the lack of antibodies to cell surface-accessible epitopes and of functional exofacially tagged CaV2 channels. Here we report the development of fully functional CaV2.2 constructs containing inserted surface-accessible exofacial tags, which allow visualization of only those channels at the plasma membrane, in both a neuronal cell line and neurons...
June 17, 2014: Proceedings of the National Academy of Sciences of the United States of America
Laurent Ferron, Manuela Nieto-Rostro, John S Cassidy, Annette C Dolphin
Fragile X syndrome (FXS), the most common heritable form of mental retardation, is characterized by synaptic dysfunction. Synaptic transmission depends critically on presynaptic calcium entry via voltage-gated calcium (Ca(V)) channels. Here we show that the functional expression of neuronal N-type Ca(V) channels (Ca(V)2.2) is regulated by fragile X mental retardation protein (FMRP). We find that FMRP knockdown in dorsal root ganglion neurons increases Ca(V) channel density in somata and in presynaptic terminals...
April 7, 2014: Nature Communications
M Nieto-Rostro, G Sandhu, C S Bauer, P Jiruska, J G R Jefferys, A C Dolphin
The auxiliary α2δ-1 subunit of voltage-gated calcium channels is up-regulated in dorsal root ganglion neurons following peripheral somatosensory nerve damage, in several animal models of neuropathic pain. The α2δ-1 protein has a mainly presynaptic localization, where it is associated with the calcium channels involved in neurotransmitter release. Relevant to the present study, α2δ-1 has been shown to be the therapeutic target of the gabapentinoid drugs in their alleviation of neuropathic pain. These drugs are also used in the treatment of certain epilepsies...
December 26, 2014: Neuroscience
Anita Alvarez-Laviada, Ivan Kadurin, Assunta Senatore, Roberto Chiesa, Annette C Dolphin
It has been shown recently that PrP (prion protein) and the calcium channel auxiliary α2δ subunits interact in neurons and expression systems [Senatore, Colleoni, Verderio, Restelli, Morini, Condliffe, Bertani, Mantovani, Canovi, Micotti, Forloni, Dolphin, Matteoli, Gobbi and Chiesa (2012) Neuron 74, 300-313]. In the present study we examined whether there was an effect of PrP on calcium currents. We have shown that when PrP is co-expressed with calcium channels formed from CaV2.1/β and α2δ-1 or α2δ-2, there is a consistent decrease in calcium current density...
March 1, 2014: Biochemical Journal
Beatrice Lana, Bettina Schlick, Stuart Martin, Wendy S Pratt, Karen M Page, Leonor Goncalves, Wahida Rahman, Anthony H Dickenson, Claudia S Bauer, Annette C Dolphin
The α2δ-1 protein is an auxiliary subunit of voltage-gated calcium channels, critical for neurotransmitter release. It is upregulated in dorsal root ganglion (DRG) neurons following sensory nerve injury, and is also the therapeutic target of the gabapentinoid drugs, which are efficacious in both experimental and human neuropathic pain conditions. α2δ-1 has 3 spliced regions: A, B, and C. A and C are cassette exons, whereas B is introduced via an alternative 3' splice acceptor site. Here we have examined the presence of α2δ-1 splice variants in DRG neurons, and have found that although the main α2δ-1 splice variant in DRG is the same as that in brain (α2δ-1 ΔA+B+C), there is also another α2δ-1 splice variant (ΔA+BΔC), which is expressed in DRG neurons and is differentially upregulated compared to the main DRG splice variant α2δ-1 ΔA+B+C following spinal nerve ligation...
March 2014: Pain
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