Ca2+- and Voltage-Dependent Inactivation of Ca2+Channels in Nerve Terminals of the Neurohypophysis

Branchaw, Janet; Banks, Matthew I.; Jackson, Meyer B.

doi:10.1523/jneurosci.17-15-05772.1997

Cited by 51 publications

(39 citation statements)

References 72 publications

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“…Voltage-dependent inactivation of Ca 2+ channels is also an important physiological mechanism regulating neurosecretion [2,14]. Several FHM-causing CACNA1A mutations alter P/Q-type calcium channel inactivation [16, 19, 20, 23, 28, this report], underlining its physiological relevance.…”

Section: Discussionmentioning

confidence: 93%

The hemiplegic migraine-associated Y1245C mutation in CACNA1A results in a gain of channel function due to its effect on the voltage sensor and G-protein-mediated inhibition

Serra

Fernàndez‐Castillo

Macaya

et al. 2009

Pflugers Arch - Eur J Physiol

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Mutations in the gene encoding the pore-forming alpha(1A) subunit of P/Q Ca(2+) channels (CACNA1A) are linked to familial hemiplegic migraine. CACNA1A Y1245C is the first missense mutation described in a subject affected with childhood periodic syndromes that evolved into hemiplegic migraine. Y1245C is also the first amino acid change described in any S1 segment of CACNA1A in a hemiplegic migraine background. We found that Y1245C induced a 9-mV left shift in the current-voltage activation curve, accelerated activation kinetics, and slowed deactivation kinetics within a wide range of voltage depolarizations. Y1245C also left-shifted the voltage-dependent steady-state inactivation with a significant increase in steepness, suggesting a direct effect on the P/Q channel voltage sensor. Moreover, Y1245C reduced Gbetagamma subunits-dependent channel inhibition probably by favoring Gbetagamma dissociation from the channel; an effect also observed using action-potential-like waveforms of different durations. The formation of a new disulfide bridge between cysteines may contribute to the Y1245C effects on activation and Gbetagamma inhibition of the channel, as they were significantly reversed by the sulphydryl-reducing agent dithiothreitol. Together, our data suggest that Y1245C alters the structure of the alpha(1A) voltage sensor producing an overall gain of channel function that may explain the observed clinical phenotypes.

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Section: Discussionmentioning

confidence: 93%

The hemiplegic migraine-associated Y1245C mutation in CACNA1A results in a gain of channel function due to its effect on the voltage sensor and G-protein-mediated inhibition

Serra

Fernàndez‐Castillo

Macaya

et al. 2009

Pflugers Arch - Eur J Physiol

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“…Voltage-dependent inactivation of Ca 2+ channels is an important physiological mechanism that contributes to the short-term depression of neurosecretion (29,30), but its contribution to migraine pathophysiology remains to be solved (5-8, 10, 11). Current density, inactivation kinetics, and voltage dependence of channel activation remained unaltered, suggesting that the effect of A454T mutation on steady-state channel inactivation is not due to the removal of Ca V β binding to the α 1A subunit (also supported by the fact that overexpression of either WT or A454T I-II loops antagonized the effect of Ca V β 2a on channel activity).…”

Section: Discussionmentioning

confidence: 99%

A mutation in the first intracellular loop of CACNA1A prevents P/Q channel modulation by SNARE proteins and lowers exocytosis

Serra

Cuenca-León²,

Llobet

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Familial hemiplegic migraine (FHM)-causing mutations in the gene encoding the P/Q Ca 2+ channel α 1A subunit (CACNA1A) locate to the pore and voltage sensor regions and normally involve gainof-channel function. We now report on a mutation identified in the first intracellular loop of CACNA1A (α 1A(A454T) ) that does not cause FHM but is associated with the absence of sensorimotor symptoms in a migraine with aura pedigree. α 1A(A454T) channels showed weakened regulation of voltage-dependent steady-state inactivation by Ca V β subunits. More interestingy, A454T mutation suppressed P/Q channel modulation by syntaxin 1A or SNAP-25 and decreased exocytosis. Our findings reveal the importance of I-II loop structural integrity in the functional interaction between P/Q channel and proteins of the vesicle-docking/fusion machinery, and that genetic variation in CACNA1A may be not only a cause but also a modifier of migraine phenotype.CaV 2.1 (P/Q) channels | SNARE proteins | migraine with aura F amilial hemiplegic migraine (FHM) is an autosomal dominantly inherited subtype of migraine with aura that features some degree of hemiparesis during attacks (1, 2). The generally accepted view on migraine pathophysiology points to cortical spreading depression (CSD), an abnormal increase of cortical activity-followed by a long-lasting neuronal suppression wavethat propagates across the cortex, as the cause of the aura and migraine itself (1, 3). FHM-causing mutations have been reported in the CACNA1A gene (encoding the P/Q Ca 2+ channel α 1 subunit) (4), resulting in a gain of P/Q channel function, mainly due to a reduction in the voltage threshold of channel activation favoring CSD initiation and propagation (1, 5-11). Other genetic and environmental factors may also play a role in shaping the phenotype, as identical mutations show different clinical characteristics (2).The P/Q Ca 2+ channel contains a pore-forming α 1A subunit and several regulatory subunits, including intracellular β subunits (Ca V β 1-4 ) that bind to the intracellular loop between transmembrane domains I and II of α 1A (see Fig. 1B for an illustration of the channel complex). The effect of the regulatory subunits is essential for increasing the expression levels and modulating the voltage-dependent activation and inactivation of P/Q channels (12-15).Presynaptic proteins of the vesicle-docking/fusion machinery, including plasma membrane SNARE proteins (syntaxin 1A and SNAP-25) and synaptotagmin, bind to a specific site (synprint) in the large intracellular loop connecting domains II and III of the P/Q channel α 1A subunit (Fig. 1B). This interaction allows secretory vesicles docking to the plasma membrane near the pathway for Ca 2+ entry, optimizing neurotransmitter release.Syntaxin 1A and SNAP-25 also exert an inhibitory effect on P/Q channel activity by left-shifting the voltage dependence of steadystate inactivation (12,16,17). The synprint site serves an important anchoring function that may facilitate SNARE's modulation of channel gating, but the involvem...

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“…Moreover, we found (iii) a switch from a monophasic to a biphasic decay of I CaL , (iv) significant contribution of Ca channels could be excluded. The role of I CaL inactivation has previously been studied in adult cardiomyocytes from fish [39], rat [40,41], rabbit [1] and guinea pig [4][5][6][7], as well as in heterologous expression systems [42,43]. In the present study we have focused in detail on the functional expression of I CaL during embryonic heart development to test whether the increase of I CaL holds also true for native murine tissue and to elaborate whether an increase in the number and/or of the open probability of L-type Ca 2+ channels may explain the increase of current.…”

Section: Discussionmentioning

confidence: 99%

Functional Expression and Inactivation of L-type Ca2+ Currents During Murine Heart Development -Implications for Cardiac Ca2+ Homeostasis

Nguemo

Fleischmann²,

Schunkert³

et al. 2007

Cell Physiol Biochem

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Ca²⁺- and Voltage-Dependent Inactivation of Ca²⁺Channels in Nerve Terminals of the Neurohypophysis

Cited by 51 publications

References 72 publications

The hemiplegic migraine-associated Y1245C mutation in CACNA1A results in a gain of channel function due to its effect on the voltage sensor and G-protein-mediated inhibition

The hemiplegic migraine-associated Y1245C mutation in CACNA1A results in a gain of channel function due to its effect on the voltage sensor and G-protein-mediated inhibition

A mutation in the first intracellular loop of CACNA1A prevents P/Q channel modulation by SNARE proteins and lowers exocytosis

Functional Expression and Inactivation of L-type Ca<sup>2+</sup> Currents During Murine Heart Development -Implications for Cardiac Ca<sup>2+</sup> Homeostasis

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