scholarly journals The structural biology of voltage-gated calcium channel function and regulation

2006 ◽  
Vol 34 (5) ◽  
pp. 887-893 ◽  
Author(s):  
F. Van Petegem ◽  
D.L. Minor
Keyword(s):  
Neurotransmitter Release ◽  
Action Potentials ◽  
Molecular Switches ◽  
Voltage Gated ◽  
Calcium Dependent ◽  
Voltage Gated Calcium Channels ◽  
Dependent Inactivation ◽  
Voltage Dependent ◽  
Soluble Calcium ◽  
Molecular Framework

Voltage-gated calcium channels (CaVs) are large (∼0.5 MDa), multisubunit, macromolecular machines that control calcium entry into cells in response to membrane potential changes. These molecular switches play pivotal roles in cardiac action potentials, neurotransmitter release, muscle contraction, calcium-dependent gene transcription and synaptic transmission. CaVs possess self-regulatory mechanisms that permit them to change their behaviour in response to activity, including voltage-dependent inactivation, calcium-dependent inactivation and calcium-dependent facilitation. These processes arise from the concerted action of different channel domains with CaV β-subunits and the soluble calcium sensor calmodulin. Until recently, nothing was known about the CaV structure at high resolution. Recent crystallographic work has revealed the first glimpses at the CaV molecular framework and set a new direction towards a detailed mechanistic understanding of CaV function.

scholarly journals Disruption of the IS6-AID Linker Affects Voltage-gated Calcium Channel Inactivation and Facilitation

2009 ◽  
Vol 133 (3) ◽  
pp. 327-343 ◽  
Author(s):  
Felix Findeisen ◽  
Daniel L. Minor
Keyword(s):  
Calcium Channel ◽  
Common Mechanism ◽  
Interaction Domain ◽  
Voltage Gated ◽  
Calcium Dependent ◽  
Calcium Channel Inactivation ◽  
Dependent Inactivation ◽  
Voltage Dependent ◽  
Rigid Connection ◽  
Voltage Gated Calcium Channel

Two processes dominate voltage-gated calcium channel (CaV) inactivation: voltage-dependent inactivation (VDI) and calcium-dependent inactivation (CDI). The CaVβ/CaVα1-I-II loop and Ca2+/calmodulin (CaM)/CaVα1–C-terminal tail complexes have been shown to modulate each, respectively. Nevertheless, how each complex couples to the pore and whether each affects inactivation independently have remained unresolved. Here, we demonstrate that the IS6–α-interaction domain (AID) linker provides a rigid connection between the pore and CaVβ/I-II loop complex by showing that IS6-AID linker polyglycine mutations accelerate CaV1.2 (L-type) and CaV2.1 (P/Q-type) VDI. Remarkably, mutations that either break the rigid IS6-AID linker connection or disrupt CaVβ/I-II association sharply decelerate CDI and reduce a second Ca2+/CaM/CaVα1–C-terminal–mediated process known as calcium-dependent facilitation. Collectively, the data strongly suggest that components traditionally associated solely with VDI, CaVβ and the IS6-AID linker, are essential for calcium-dependent modulation, and that both CaVβ-dependent and CaM-dependent components couple to the pore by a common mechanism requiring CaVβ and an intact IS6-AID linker.

scholarly journals Functions of Presynaptic Voltage-gated Calcium Channels

Function ◽  
2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Annette C Dolphin
Keyword(s):  
Calcium Channels ◽  
Neurotransmitter Release ◽  
Action Potentials ◽  
Voltage Dependence ◽  
Kinetic Properties ◽  
Excitable Cells ◽  
Single Action ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Vesicular Release

Abstract Voltage-gated calcium channels are the principal conduits for depolarization-mediated Ca2+ entry into excitable cells. In this review, the biophysical properties of the relevant members of this family of channels, those that are present in presynaptic terminals, will be discussed in relation to their function in mediating neurotransmitter release. Voltage-gated calcium channels have properties that ensure they are specialized for particular roles, for example, differences in their activation voltage threshold, their various kinetic properties, and their voltage-dependence of inactivation. All these attributes play into the ability of the various voltage-gated calcium channels to participate in different patterns of presynaptic vesicular release. These include synaptic transmission resulting from single action potentials, and longer-term changes mediated by bursts or trains of action potentials, as well as release resulting from graded changes in membrane potential in specialized sensory synapses.

scholarly journals Voltage control of Ca2+ permeation through N-type calcium (CaV2.2) channels

2014 ◽  
Vol 144 (3) ◽  
pp. 207-220 ◽  
Author(s):  
Zafir Buraei ◽  
Haoya Liang ◽  
Keith S. Elmslie
Keyword(s):  
Binding Sites ◽  
Neurotransmitter Release ◽  
Action Potentials ◽  
Channel Blocker ◽  
Cellular Functions ◽  
Voltage Gated ◽  
High Affinity ◽  
Step Model ◽  
Independent Test ◽  
Voltage Dependent

Voltage-gated calcium (CaV) channels deliver Ca2+ to trigger cellular functions ranging from cardiac muscle contraction to neurotransmitter release. The mechanism by which these channels select for Ca2+ over other cations is thought to involve multiple Ca2+-binding sites within the pore. Although the Ca2+ affinity and cation preference of these sites have been extensively investigated, the effect of voltage on these sites has not received the same attention. We used a neuronal preparation enriched for N-type calcium (CaV2.2) channels to investigate the effect of voltage on Ca2+ flux. We found that the EC50 for Ca2+ permeation increases from 13 mM at 0 mV to 240 mM at 60 mV, indicating that, during permeation, Ca2+ ions sense the electric field. These data were nicely reproduced using a three-binding-site step model. Using roscovitine to slow CaV2.2 channel deactivation, we extended these measurements to voltages <0 mV. Permeation was minimally affected at these hyperpolarized voltages, as was predicted by the model. As an independent test of voltage effects on permeation, we examined the Ca2+-Ba2+ anomalous mole fraction (MF) effect, which was both concentration and voltage dependent. However, the Ca2+-Ba2+ anomalous MF data could not be reproduced unless we added a fourth site to our model. Thus, Ca2+ permeation through CaV2.2 channels may require at least four Ca2+-binding sites. Finally, our results suggest that the high affinity of Ca2+ for the channel helps to enhance Ca2+ influx at depolarized voltages relative to other ions (e.g., Ba2+ or Na+), whereas the absence of voltage effects at negative potentials prevents Ca2+ from becoming a channel blocker. Both effects are needed to maximize Ca2+ influx over the voltages spanned by action potentials.

scholarly journals A CACNA1A variant associated with trigeminal neuralgia alters the gating of Cav2.1 channels

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Eder Gambeta ◽  
Maria A. Gandini ◽  
Ivana A. Souza ◽  
Laurent Ferron ◽  
Gerald W. Zamponi
Keyword(s):  
Trigeminal Neuralgia ◽  
Missense Mutation ◽  
Neurotransmitter Release ◽  
Trigeminal System ◽  
Wild Type ◽  
Calcium Dependent ◽  
Whole Cell Patch Clamp ◽  
C Terminus ◽  
Dependent Inactivation

AbstractA novel missense mutation in the CACNA1A gene that encodes the pore forming α1 subunit of the CaV2.1 voltage-gated calcium channel was identified in a patient with trigeminal neuralgia. This mutation leads to a substitution of proline 2455 by histidine (P2455H) in the distal C-terminus region of the channel. Due to the well characterized role of this channel in neurotransmitter release, our aim was to characterize the biophysical properties of the P2455H variant in heterologously expressed CaV2.1 channels. Whole-cell patch clamp recordings of wild type and mutant CaV2.1 channels expressed in tsA-201 cells reveal that the mutation mediates a depolarizing shift in the voltage-dependence of activation and inactivation. Moreover, the P2455H mutant strongly reduced calcium-dependent inactivation of the channel that is consistent with an overall gain of function. Hence, the P2455H CaV2.1 missense mutation alters the gating properties of the channel, suggesting that associated changes in CaV2.1-dependent synaptic communication in the trigeminal system may contribute to the development of trigeminal neuralgia.

Altered frequency-dependent inactivation and steady-state inactivation of polyglutamine-expanded α1A in SCA6

2007 ◽  
Vol 292 (3) ◽  
pp. C1078-C1086 ◽  
Author(s):  
Haiyan Chen ◽  
Erika S. Piedras-Rentería
Keyword(s):  
Steady State ◽  
Late Onset ◽  
Spinocerebellar Ataxia Type ◽  
Gain Of Function ◽  
Calcium Dependent ◽  
Spinocerebellar Ataxia Type 6 ◽  
Dependent Inactivation ◽  
Voltage Dependent ◽  
Steady State Inactivation ◽  
Activity Dependent

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease of the cerebellum and inferior olives characterized by a late-onset cerebellar ataxia and selective loss of Purkinje neurons ( 15 , 16 ). SCA6 arises from an expansion of the polyglutamine tract located in exon 47 of the α1A (P/Q-type calcium channel) gene from a nonpathogenic size of 4 to 18 glutamines (CAG4–18) to CAG19–33 in SCA6. The molecular basis of SCA6 is poorly understood. To date, the biophysical properties studied in heterologous systems support both a gain and a loss of channel function in SCA6. We studied the behavior of the human α1A isoform, previously found to elicit a gain of function in disease ( 41 ), focusing on properties in which the COOH terminus of the channel is critical for function: we analyzed the current properties in the presence of β4- and β2a-subunits (both known to interact with the α1A COOH terminus), current kinetics of activation and inactivation, calcium-dependent inactivation and facilitation, voltage-dependent inactivation, frequency dependence, and steady-state activation and inactivation properties. We found that SCA6 channels have decreased activity-dependent inactivation and a depolarizing shift (+6 mV) in steady-state inactivation properties consistent with a gain of function.

Calcium- and Calmodulin-Dependent Inactivation of Calcium Channels in Inner Hair Cells of the Rat Cochlea

2008 ◽  
Vol 99 (5) ◽  
pp. 2183-2193 ◽  
Author(s):  
Lisa Grant ◽  
Paul Fuchs
Keyword(s):  
Calcium Channels ◽  
Hair Cells ◽  
Calcium Currents ◽  
Resting Potential ◽  
Resting Membrane Potential ◽  
Inner Hair Cells ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Dependent Inactivation ◽  
Calcium Buffering

Modulation of voltage-gated calcium channels was studied in inner hair cells (IHCs) in an ex vivo preparation of the apical turn of the rat organ of Corti. Whole cell voltage clamp in the presence of potassium channel blockers showed inward calcium currents with millisecond activation and deactivation kinetics. When temperature was raised from 22 to 37°C, the calcium currents of immature IHCs [<12 days postnatal (P12)] increased threefold in amplitude, and developed more pronounced inactivation. This was determined to be calcium-dependent inactivation (CDI) on the basis of its reliance on external calcium (substitution with barium), sensitivity to internal calcium-buffering, and voltage dependence (reflecting the calcium driving force). After the onset of hearing at P12, IHC calcium current amplitude and the extent of inactivation were greatly reduced. Although smaller than in prehearing IHCs, CDI remained significant in the mature IHC near the resting membrane potential. CDI in mature IHCs was enhanced by application of the endoplasmic calcium pump blocker, benzo-hydroquinone. Conversely, CDI in immature IHCs was reduced by calmodulin inhibitors. Thus voltage-gated calcium channels in mammalian IHCs are subject to a calmodulin-mediated process of CDI. The extent of CDI depends on the balance of calcium buffering mechanisms and may be regulated by calmodulin-specific processes. CDI provides a means for the rate of spontaneous transmitter release to be adjusted to variations in hair cell resting potential and steady state calcium influx.

scholarly journals Action Potentials in Rhodnius Oocytes: Repolarization is Sensitive to Potassium Channel Blockers

1986 ◽  
Vol 126 (1) ◽  
pp. 119-132
Author(s):  
M. J. O'DONNELL
Keyword(s):  
Potassium Channel ◽  
Action Potentials ◽  
Potassium Conductance ◽  
Channel Blockers ◽  
Calcium Dependent ◽  
Outward Rectification ◽  
Current Voltage ◽  
Potassium Channel Blockers ◽  
Potassium Conductances ◽  
Voltage Dependent

Depolarization of Rhodnius oocytes evokes action potentials (APs) whose rising phase is calcium-dependent. The ionic basis for the repolarizing (i.e. falling) phase of the AP was examined. Addition of potassium channel blockers (tetraethylammonium, tetrabutylammonium, 4-aminopyridine, atropine) to the bathing saline increased the duration and overshoot of APs. Intracellular injection of tetraethyl ammonium had similar effects. These results suggest that a voltage-dependent potassium conductance normally contributes to repolarization. Repolarization does not require a chloride influx, because substitution of impermeant anions for chloride did not increase AP duration. AP duration and overshoot actually decreased progressively when chloride levels were reduced. Current/voltage curves show inward and outward rectification, properties often associated with potassium conductances. Outward rectification was largely blocked by external tetraethylammonium. Possible functions of the rectifying properties of the oocyte membrane are discussed.

Effects of Octopamine on Calcium Action Potentials in Insect Oocytes

1989 ◽  
Vol 142 (1) ◽  
pp. 115-124
Author(s):  
M. J. O'DONNELL ◽  
B. SINGH
Keyword(s):  
Action Potentials ◽  
Rank Order ◽  
Potassium Conductance ◽  
Membrane Resistance ◽  
Threshold Concentration ◽  
Resting Potential ◽  
Calcium Dependent ◽  
Octopamine Receptors ◽  
Voltage Dependent ◽  
Maximum Rate Of Rise

Our experiments show that octopamine receptors are present on the developing follicles of an insect, Rhodnius prolixus. Application of D,L-octopamine decreased the duration and overshoot of calcium-dependent action potentials (APs), and increased the intrafollicular concentration of cyclic AMP. The threshold concentration of D,L-octopamine for the reduction in electrical excitability was between 1 and 5×10−7moll−1, and maximal effects of a 40–50% reduction in AP overshoot and duration were apparent at 10−4moll−1. At concentrations above 10−5moll−1, a small (&lt;10%) hyperpolarization of the resting potential was also apparent. Effects of D,L-octopamine on oocyte excitability were independent of these small shifts in resting potential. Current injection experiments, in which calcium entry was blocked by cobalt, demonstrated that D,L-octopamine reduced membrane resistance at both hyperpolarizing and depolarizing potentials. Octopamine did not affect the maximum rate of rise of the AP, dV/dtmax, which is an indicator of inward calcium current. It is suggested that octopamine may mediate its effects on excitability through an increase in a voltage-dependent potassium conductance. Application of other phenolamines indicated a rank order of potency of D, Loctopamine &gt; D,L-synephrine &gt; tyramine. The α-adrenergic agonists clonidine, naphazoline and tolazoline were without significant effect at 10−5-10−3moll−1. Reduction of excitability by D,L-octopamine was effectively blocked by phentolamine and metoclopramide. Yohimbine and gramine were less effective as antagonists. Possible functions of octopamine receptors in insect follicles are discussed.

scholarly journals A Selectivity Filter Gate Controls Voltage-Gated Calcium Channel Calcium-Dependent Inactivation

Neuron ◽  
2019 ◽  
Vol 101 (6) ◽  
pp. 1134-1149.e3 ◽  
Author(s):  
Fayal Abderemane-Ali ◽  
Felix Findeisen ◽  
Nathan D. Rossen ◽  
Daniel L. Minor
Keyword(s):  
Calcium Channel ◽  
Selectivity Filter ◽  
Voltage Gated ◽  
Calcium Dependent ◽  
Dependent Inactivation ◽  
Voltage Gated Calcium Channel
Sign in / Sign up

Export Citation Format

Share Document