Developmental expression of neuronal nitric oxide synthase in P/Q-type voltage-gated calcium ion channel mutant mice, leaner and tottering

Frank-Cannon, Tamy C.; Zeve, Daniel; Abbott, Louise C.

doi:10.1016/j.brainres.2005.10.082

Cited by 3 publications

(1 citation statement)

References 48 publications

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“…Alterations in a number of other proteins have also been reported, some of which may contribute to the motor dysfunction in the mutant (Hess and Wilson, 1991;Austin et al, 1992;Fureman et al, 1999;Sawada and Fukui, 2001;Cicale et al, 2002;Frank-Cannon et al, 2007). In the case of tyrosine hydroxylase (TH), aberrations in calcium channel influx in tottering appear to precipitate abnormal developmental control of expression.…”

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Altered functional expression of Purkinje cell calcium channels precedes motor dysfunction in tottering mice

et al. 2007

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In tottering mice, a point mutation in the gene encoding P-type (Ca(v)2.1) voltage-gated calcium channels results in ataxia, absence epilepsy, and motor dystonia that appear 3-4 weeks postnatally. The aberrant motor behaviors have been linked to cerebellar dysfunction, and adult Purkinje cells (PCs) of tottering mice exhibit calcium-dependent changes in gene transcription suggestive of altered calcium homeostasis. In an attempt to identify early postnatal events important for the development of the behavioral phenotype, we examined calcium channel expression in cerebellar PCs from postnatal days 6-15 (P6-15). Whole cell recording was combined with selective calcium channel antagonists to allow discrimination of the various voltage-activated calcium channels types; early age-dependent differences between tottering and wild-type PCs were found. Wild-type PCs experienced a steady increase in P current density over this period, resulting in a twofold change by P15. In tottering, by contrast, P current density remained unchanged from P6-8 and was only 25% of the wild-type level by P8. A developmental delay in functional expression was implicated in this early deficit, since ensuing gains over the subsequent week brought tottering P current density close to the wild-type level by P15. At this age, tottering PCs also exhibited a 2.2-fold higher L-type calcium current density than that expressed by wild-type PCs. Increases in N current were apparent at some ages, most strikingly within a subset of tottering PCs at P15. Functional R- and T-type calcium current densities were equivalent to wild-type levels at all ages. We conclude that the tottering mutation brings about selective changes in functional calcium channel expression 1 to 2 weeks prior to the appearance of the behavioral deficits, raising the possibility that they represent an early, primary event along the path to motor dysfunction in tottering.

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Altered functional expression of Purkinje cell calcium channels precedes motor dysfunction in tottering mice

et al. 2007

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The Regulation of a Cell’s Ca2+ Signaling Toolkit: The Ca2+ Homeostasome

Schwaller

2012

Advances in Experimental Medicine and Biology

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The Ca(2+) ion serves as a ubiquitous second messenger in eukaryotic cells and changes in the intracellular Ca(2+) concentration regulate many responses within a cell, but also communication between cells. In order to make use of such an apparently simple signal, i.e. a change in the intracellular Ca(2+) concentration, cells are equipped with sophisticated machinery to precisely regulate the shape (amplitude, duration) of Ca(2+) signals in a localization-specific manner. To ascertain such a precise regulation, cells rely on the components of the Ca(2+) signaling toolkit. This embraces Ca(2+) entry systems including Ca(2+) channels in the plasma membrane and organellar membranes, and Ca(2+) extrusion/uptake systems including Ca(2+)-ATPases (Ca(2+) pumps) and Na(+)/Ca(2+) exchangers. Besides mitochondria, organelles implicated also in Ca(2+) signaling, cytosolic Ca(2+) buffers are cell-specific subtle modulators of Ca(2+) signals. The Ca(2+)-signaling components not only orchestrate their activity as to ascertain the high accuracy of intracellular Ca(2+) signaling, but they are also implicated in the regulation of their own expression. The total of the molecules that build the network of Ca(2+) signaling components, and that are involved in their own regulation as to maintain physiological Ca(2+) homeostasis resulting in phenotypic stability is named the Ca(2+) homeostasome. Mechanistic details on the functioning of the Ca(2+) homeostasome are presented.

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Abnormal Excitability and Episodic Low-Frequency Oscillations in the Cerebral Cortex of thetotteringMouse

et al. 2015

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The Ca 2ϩ channelopathies caused by mutations of the CACNA1A gene that encodes the pore-forming subunit of the human Ca v 2.1 (P/Q-type) voltage-gated Ca 2ϩ channel include episodic ataxia type 2 (EA2). Although, in EA2 the emphasis has been on cerebellar dysfunction, patients also exhibit episodic, nonmotoric abnormalities involving the cerebral cortex. This study demonstrates episodic, low-frequency oscillations (LFOs) throughout the cerebral cortex of tottering (tg/tg) mice, a widely used model of EA2. Ranging between 0.035 and 0.11 Hz, the LFOs in tg/tg mice can spontaneously develop very high power, referred to as a high-power state. The LFOs in tg/tg mice are mediated in part by neuronal activity as tetrodotoxin decreases the oscillations and cortical neuron discharge contain the same low frequencies. The high-power state involves compensatory mechanisms because acutely decreasing P/Q-type Ca 2ϩ channel function in either wild-type (WT) or tg/tg mice does not induce the high-power state. In contrast, blocking L-type Ca 2ϩ channels, known to be upregulated in tg/tg mice, reduces the high-power state. Intriguingly, basal excitatory glutamatergic neurotransmission constrains the high-power state because blocking ionotropic or metabotropic glutamate receptors results in high-power LFOs in tg/tg but not WT mice. The high-power LFOs are decreased markedly by acetazolamide and 4-aminopyridine, the primary treatments for EA2, suggesting disease relevance. Together, these results demonstrate that the high-power LFOs in the tg/tg cerebral cortex represent a highly abnormal excitability state that may underlie noncerebellar symptoms that characterize CACNA1A mutations.

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Developmental expression of neuronal nitric oxide synthase in P/Q-type voltage-gated calcium ion channel mutant mice, leaner and tottering

Cited by 3 publications

References 48 publications

Altered functional expression of Purkinje cell calcium channels precedes motor dysfunction in tottering mice

Altered functional expression of Purkinje cell calcium channels precedes motor dysfunction in tottering mice

The Regulation of a Cell’s Ca2+ Signaling Toolkit: The Ca2+ Homeostasome

Abnormal Excitability and Episodic Low-Frequency Oscillations in the Cerebral Cortex of thetotteringMouse

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