Hugo William Tedford

The University of Calgary · Department of Clinical Neurosciences

As in neurons, CNS myelin expresses N-Methyl-D-Aspartate Receptors (NMDARs) that subserve physiological roles, but have the potential to induce injury to this vital element. Using 2-photon imaging of myelinic Ca in live ex vivo mouse optic nerves, we show that Cu ions potently modulate Ca levels in an NMDAR-dependent manner. Chelating Cu in the per...

Despite intensive control measures, insect pests cause enormous damage to crops and stored grain. In addition, insects vector some of the world's most devastating human diseases, including malaria, dengue and Chagas disease. Chemical insecticides remain the dominant method of controlling insect pests but the arsenal of extant insecticides is rapidl...

Previously, scanning mutagenesis studies of the insecticidal peptide omega-hexatoxin-Hv1a identified a set of structural features used by the omega-hexatoxin-1 family to modulate insect calcium channels. These structural features were re-purposed as a 3D search term (i.e., a pharmacophore model) for mining commercially available compound databases,...

It is generally accepted that the immediately releasable pool is a group of readily releasable vesicles that are closely associated with voltage dependent Ca(2+) channels. We have previously shown that exocytosis of this pool is specifically coupled to P/Q Ca(2+) current. Accordingly, in the present work we found that the Ca(2+) current flowing thr...

Rat versus mouse synprint homology analysis. Based on the comparison, these segments of the synprint region are 93% identical and 94.7% similar between rat and mouse, with eight gaps in alignment due to the rat synprint isoform in question being longer. (PDF)

A. The bar diagram compares the averaged Ca2+ currents densities in control conditions and in the presence of AGA (replications of Fig. 2B) with a group of experiments with high Ca2+ current densities in presence of AGA (we selected 3 cells from the experiments represented in Fig. 2B and C, and added 4 new cells, all with currents higher than 20 pA...

A. Examples of DIC Nomarsky images and associated confocal EGFP fluorescence images of two fixed chromaffin cells transfected with the synprint-pIRES2-EGFP plasmid. B. Examples of cellular P/Q-type channel distribution for control and Syn+ cells. The cells were fixed in 2% paraformaldehyde and permeabilized with 0.5% Tween 20. Subsequently, the cel...

Examples of ICa2+ induced by 50 ms depolarizations (from −80 to +10 mV) obtained on the same cell in control conditions (black), and with consecutive additions of 200 nM AGA (gray), and AGA +10 µM Nitre (light gray). (PDF)

A. Examples of original capacitance records obtained in response to the application of a 10 ms dual pulse protocol for the estimation of the IRP in cells dialyzed with (i) 0.5 mM EGTA or (ii) 0.5 mM BAPTA. B. Original capacitance records obtained in response to the application of a 100 ms dual pulse protocol for the estimation of the RRP in cells d...

It is well established that the auxiliary Cavβ subunit regulates calcium channel density in the plasma membrane, but the cellular mechanism by which this occurs has remained unclear. We found that the Cavβ subunit increased membrane expression of Cav1.2 channels by preventing the entry of the channels into the endoplasmic reticulum-associated prote...

Direct interaction with the beta subunit of the heterotrimeric G protein complex causes voltage-dependent inhibition of N-type calcium channels. To further characterize the molecular determinants of this interaction, we performed scanning mutagenesis of residues 372-387 and 410-428 of the N-type channel alpha1 subunit, in which individual residues...

Insects are the most diverse and successful animals on the planet, with the number of extant species estimated to be not, vert, similar5 million (Novotny et al., 2002). However, the ability of insects to inhabit a wide variety of ecological niches has inevitably brought them into conflict with humans. Although only a small minority of insects are c...

We have developed a model genetic system for analyzing the function of peptide toxins from animal venoms. We engineered and propagated strains of Drosophila melanogaster expressing heat-inducible transgenes encoding either kappa-ACTX-Hv1c or omega-ACTX-Hv1a, two insect-specific neurotoxic peptides found in the venom of the Australian funnel-web spi...

The regulation of presynaptic, voltage-gated calcium channels by activation of heptahelical G protein-coupled receptors exerts a crucial influence on presynaptic calcium entry and hence on neurotransmitter release. Receptor activation subjects presynaptic N- and P/Q-type calcium channels to a rapid, membrane-delimited inhibition-mediated by direct,...

Direct interactions between the presynaptic N-type calcium channel and the beta subunit of the heterotrimeric G-protein complex cause voltage-dependent inhibition of N-type channel activity, crucially influencing neurotransmitter release and contributing to analgesia caused by opioid drugs. Previous work using chimeras of the G-protein beta subtype...

We constructed a complete panel of alanine mutants of the insect-specific calcium channel blocker omega-atracotoxin-Hv1a. Lethality assays using these mutant toxins identified three spatially contiguous residues, Pro10, Asn27, and Arg35, that are critical for insecticidal activity against flies (Musca domestica) and crickets (Acheta domestica). Com...

Arthropods are the most diverse animal group on the planet. Their ability to inhabit a vast array of ecological niches has inevitably brought them into conflict with humans. Although only a small minority are classified as pest species, they nevertheless destroy about a quarter of the world's annual crop production and transmit an impressive array...

The ω-atracotoxin-1 (ω-ACTX-1) neurotoxins are 36-37-residue peptides found in the venom of all species of Australian funnel-web spiders examined to date. The prototypic family member, ω-ACTX-Hv1a, is lethal to a wide range of insects and potently antagonizes high-voltage activated (HVA) calcium channels--a component of the insect nervous system ne...

The outer dynein arm from Chlamydomonas flagella contains two redox-active thioredoxin-related light chains associated with the alpha and beta heavy chains; these proteins belong to a distinct subgroup within the thioredoxin family. This observation suggested that some aspect of dynein activity might be modulated through redox poise. To test this,...

Insect pests decimate a significant proportion of the world's food supply and transmit a number of deadly human diseases. These arthropods are generally controlled by spraying broadspectrum chemical insecticides. However, the emergence of insecticide-resistant insect populations, as well as increasing disquiet about the environmental and human heal...

omega-Atracotoxin-Hv1a is an insect-specific neurotoxin whose phylogenetic specificity derives from its ability to antagonize insect, but not vertebrate, voltage-gated calcium channels. In order to help understand its mechanism of action and to enhance its utility as a lead compound for insecticide development, we used a combination of protein engi...

The Tctex1/Tctex2 family of dynein light chains associates with the intermediate chains at the base of the soluble dynein particle. These components are essential for dynein assembly and participate in specific motor-cargo interactions. To further address the role of these light chains in dynein activity, the structural and biochemical properties o...

In the filamentous fungus Aspergillus nidulans, germination of an asexual conidiospore results in the formation of a hyphal cell. A key feature of spore germination is the switch from isotropic spore expansion to polarized apical growth. Here, temperature-sensitive mutations are used to characterize the roles of five genes (sepA, hypA, podB-podD) i...