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Characterization and identifiction of low affinity dihydropyridine binding sites on skeletal muscle Ca[superscript 2]+ channels /Bao, Dingjiu. January 1997 (has links) (PDF)
Thesis (M.Sc.)--University of Alberta, 1997. / Submitted to the Faculty of Graduate Studies and Research in partial fulfilment of the requirements for the degree of Master of Science, Division of Neuroscience. Also available online.
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Differentiation of Cav1.2 and Cav1.3 pharmacology and role of RyR2 in pancreatic beta-cell electrophysiologyShiqi Tang (11134677) 22 July 2021 (has links)
<p></p><p>The<b> </b>L-type
VGCC subtypes, including subtypes Ca<sub>v</sub>1.1-1.4, have
been shown to play critical roles in various cellular activities, including
muscle contraction, hormone secretion, and neurotransmitter release. Recent research indicates the potential involvement
of Ca<sub>v</sub>1.3 in various neurological and psychiatric disorders, such as
the early onset of Parkinson’s disease and substance abuse disorders. Non-selective
L-VGCC subtype blockers such as dihydropyridines (DHPs) are used to treat
hypertension and angina because they potently inhibit Ca<sub>v</sub>1.2, but no
selective Ca<sub>v</sub>1.3 inhibitors have been developed yet. We resolved the molecular
determinants to differentiate Ca<sub>v</sub>1.2 and Ca<sub>v</sub>1.3
in response to DHP nifedipine.
Nifedipine IC<sub>50</sub> for Ca<sub>v</sub>1.2 and Ca<sub>v</sub>1.3 are 22nM
and 289nM determined by whole-cell patch-clamp. We identified two significant amino
acids, Ca<sub>v</sub>1.3/M1030 to Ca<sub>v</sub>1.2/V1036 in the transmembrane
IIIS5 and Ca<sub>v</sub>1.3/S1100 Ca<sub>v</sub>1.2/A1106 in the extracellular
IIIS-3P loop, to differentiate the subtype affinity to nifedipine. </p>
<p>We
found that the Ca<sub>v</sub>1.3/II-III loop fused to eGFP decreased
glucose-activated action potential (GSAP) frequency by ~80% in the pancreatic
β-cell. We introduced several synthetic peptides, and peptide P3-1 from C-terminal
induced a -16mV shift in V<sub>1/2</sub> inactivation
with an EC<sub>50</sub> of 231nM. P3-1 contains a protein kinase G (PKG)
phosphorylation site (RRISE) required for PKG inhibition of Ca<sub>v</sub>1.3
current but not conserved in Ca<sub>v</sub>1.2. We found that the shift in V<sub>1/2</sub>
inactivation induced by co-expression of Ca<sub>v</sub>1.3 with the Ca<sub>v</sub>1.3/II-III
loop/GFP requires the presence of a Ca<sub>v</sub>β subunit, and Ca<sub>v</sub>β<sub>3</sub>
also exhibits selectivity over other β subunits. Significantly, P3-1 shifts the
Ca<sub>v</sub>1.2 inactivation to a more positive voltage when co-expressed
with either Ca<sub>v</sub>β<sub>2a </sub>or Ca<sub>v</sub>β<sub>3</sub>, demonstrating
the ability of P3-1 to differentiate Ca<sub>v</sub>1.2 and Ca<sub>v</sub>1.3 in
a Ca<sub>v</sub>β-dependent manner.</p>
<p><b> </b>Failure of pancreatic β-cells to secrete enough insulin to maintain glucose
homeostasis is a hallmark of Type 2 diabetes. However, the consequences of the dysregulation
of the endoplasmic reticulum (ER) Ca<sup>2+</sup> channel ryanodine receptor-2
(RyR2) in pancreatic β-cells are not fully understood. Therefore, we characterized
the electrical activity in INS-1 in which RyR2 has been deleted via CRISPR/Cas9
gene editing. We observed a decreased level of IP<sub>3</sub> receptor binding
protein (IRBIT) in RyR2<sup>KO</sup> INS-1 cells and generated IRBIT<sup>KO</sup>
INS-1 cells. VGCC current density in RyR2<sup>KO</sup> doubled compared to controls and was
also elevated in IRBIT<sup>KO </sup>compared to control cells. All HVA Ca<sup>2+</sup>
channels were upregulated, determined by fractional current blocked by
nifedipine. We also
found that GSAP frequency is doubled by RyR2 deletion due to failure to
activate apamin sensitive SK (small conductance calcium-activated potassium)
channels. </p><br><p></p>
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Effects of passive avoidance training on calcium flux in chicken forebrainChaudhury, Dipesh January 1999 (has links)
No description available.
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Neurodegeneration in cerebellar granule cells of p/q type voltage gated calcium channel mutant leaner miceBawa, Bhupinder 15 May 2009 (has links)
Mutations of the α1A subunit of CaV 2.1 voltage gated calcium (VGCC) channels
are responsible for several inherited disorders affecting humans, including familial
hemiplegic migraine, episodic ataxia type and spinocerebellar ataxia type. The leaner
mouse also carries an autosomal recessive mutation in the α1A subunit of CaV 2.1 VGCCs,
which, in the homozygous condition, results in a severe cerebellar atrophy and ataxia.
The leaner mutation results in reduced calcium influx through CaV 2.1 VGCCs. To better
understand cerebellar neurodegeneration and cerebellar dysfunction we focused our
research on elucidating the relationship between mitochondrial function/dysfunction and
calcium channel mutations. The aims of this dissertation were: 1) to estimate the extent
of neuronal cell death, basal intracellular calcium and mitochondrial (dys)function in
cerebellar granule cells (CGC) of adult leaner mice; 2) to analyze the role of the leaner
calcium channel mutation on postnatal development of CGCs; and 3) to test whether
inducing increased calcium influx by exposing cultured granule cells to potassium
chloride can eliminate or reduce the CGC death. By using mechanism independent Fluoro-Jade staining and apoptosis specific
TUNEL staining, we demonstrated that leaner CGC death continues into adulthood and
the spatial pattern of granule cell death observed during postnatal development also
continues into adulthood. The present investigation showed a reduced resting
intracellular calcium in CGC from leaner mice as compared to age matched wild type
mice, and tottering mice. The tottering mouse is another mutant mouse that carries a
mutation in the α1A subunit of CaV 2.1 VGCCs like leaner mouse. However, these mice
do not show any neurodegeneration and therefore they were used as a second control.
Our results also showed that even though CGC of leaner mice have dysfunctional CaV2.1
channels, there is no change in depolarization induced Ca2+ influx, which suggests a
functional compensation for CaV2.1 calcium channels by other VGCCs. Our results
showed reduced mitochondrial membrane potential at the time of peak CGC death in
leaner mice as compared to wild type CGCs and tottering CGCs. The results of this
investigation suggest mitochondrial mediated but reactive oxygen species independent
cell death in CGCs of leaner mice.
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Structural determinants of G-protein modulation of neuronal calcium channels /Simen, Arthur A. January 1999 (has links)
Thesis (Ph. D.)--University of Chicago, Committee on Neurobiology, August 1999. / Includes bibliographical references. Also available on the Internet.
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Targeting of voltage-gated calcium channels to lipid rafts : the role of auxiliary alpha2/delta-1 subunitsRobinson, Philip January 2011 (has links)
Ca2+ entry through voltage-gated calcium channels (CaVs) triggers a range of physiological events, including synaptic neurotransmission and muscular excito-contraction coupling. CaVs are often localised to discrete membrane microdomains and are required to be targeted to such fine structures in order to perform their cellular functions. CaVs are multi-subunit protein complexes that consist of a core, pore-forming α1 subunit and auxiliary β and α2/δ subunits. The α2/δ subunit is required for the optimal cell surface expression and function of CaVs and is itself localised to cholesterol-rich membrane microdomains called lipid rafts. What is unclear is whether the α2/δ subunit is required for whole CaV complexes to be localised to lipid rafts and what effects lipid raft association has on the cell surface distribution and function of CaVs. By a combination of cellular imaging, biochemistry and electrophysiology, this project shows that the auxiliary α2/δ-1 subunit is both necessary and sufficient to target CaV2.2 to lipid rafts in the COS-7 cell heterologous expression system (Robinson et al, 2010). In addition, α2/δ is localised at the cell surface in discrete puncta and co-localises with two endogenous lipid raft resident proteins, caveolin and flotillin-1. While the punctate cell surface distribution of α2/δ is co-incident with that of caveolin and flotillin-1, its distribution is not dependent on cellular cholesterol, but rather the integrity of the actin cytoskeleton. Additional structure-function analysis by employment of the pIN-α2/δ series of deletion and substitution mutants has shown that the association of α2/δ with lipid rafts is bestowed by an extracellular region of the delta peptide, contrary to other evidence supporting the notion that α2/δ may be a GPI-anchored protein. The exact physiological and functional significance of α2/δ and CaV association with lipid rafts remains poorly understood, but the fact that CaVs are enriched within these fine structures provides a potential mechanism for targeting and access to lipid raft associated signalling pathways.
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Toxicological evaluation of p, p'-DDT and its analogs on the calcium channel of the ciliate organism Paramecium tetraurelia.Frederick, Kosea S. 01 January 2000 (has links) (PDF)
No description available.
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Characterization of the action of pyrethroids on the ciliary calcium channel of Paramecium tetraurelia.Symington, Steven B. 01 January 2000 (has links) (PDF)
No description available.
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An electrophysiological and pharmacological characterization of a Ca'2'+ channel currents in the soma and dendrites of adult rat cerebellar Purkinje cellsDupere, Jonathan R. B. January 1997 (has links)
No description available.
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The pharmacology of the sheep cardiac sarcoplasmic reticulum Ca'2'+-release channelMcGarry, Stephen James January 1994 (has links)
No description available.
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