Calcium channel selectivity for divalent and monovalent cations. Voltage and concentration dependence of single channel current in ventricular heart cells.

Hess, Peter; Lansman, Jeffry B.; Tsien, Richard W.

doi:10.1085/jgp.88.3.293

Cited by 557 publications

(388 citation statements)

References 42 publications

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“…As previously reported for L-type (Hess, Lansman, and Tsien, 1986) and N-type channels (Carbone and Lux, 1988;Jones and Marks, 1989), we found that the to-CgTx-sensitive channels of chick DRG neurons became significantly permeant to monovalent cations when the extracellular Ca 2+ concentration was reduced below micromolar levels. When no divalent cations were added to the extracellular solution and 1 mM EGTA was included, a sustained inward current was observed upon depolarization to potentials more positive than -55 mV.…”

Section: N Current Carried By Na +supporting

confidence: 87%

Inactivation of N-type calcium current in chick sensory neurons: calcium and voltage dependence.

Cox

Dunlap

1994

The Journal of General Physiology

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We have studied the inactivation of high-voltage-activated (HVA), t0-conotoxin-sensitive, N-type Ca 2+ current in embryonic chick dorsal root ganglion (DRG) neurons. Voltage steps from -80 to 0 mV produced inward Ca ~+ currents that inactivated in a biphasic manner and were fit well with the sum of two exponentials (with time constants of ~ 100 ms and > 1 s). As reported previously, upon depolarization of the holding potential to -40 mV, N current amplitude was significantly reduced and the rapid phase of inactivation all but eliminated (Nowycky, M. C., A. P. Fox, and R. W. be explained by a model in which N channels inactivate by both fast and slow voltage-dependent processes. Alternatively, kinetic models of Ca-dependent inactivation suggest that the biphasic kinetics and holding-potential-dependence of N current inactivation could be due to a combination of Ca-dependent and slow voltage-dependent inactivation mechanisms. To distinguish between these possibilities we have performed several experiments to test for the presence of Cadependent inactivation. Three lines of evidence suggest that N channels inactivate in a Ca-dependent manner. (a) The total extent of inactivation increased 50%, and the ratio of rapid to slow inactivation increased ~ twofold when the concentration of the Ca 2 § buffer, EGTA, in the patch pipette was reduced from 10 to 0.1 mM. (b) With low intracellular EGTA concentrations (0.1 mM), the ratio of rapid to slow inactivation was additionally increased when the extracellular Ca 2 § concentration was raised from 0.5 to 5 mM. (c) Substituting Na § for Ca 2 § as the permeant ion eliminated the rapid phase of inactivation. Other results do not support the notion of current-dependent inactivation, however. Although high intraceUular EGTA (10

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Section: N Current Carried By Na +supporting

confidence: 87%

Inactivation of N-type calcium current in chick sensory neurons: calcium and voltage dependence.

Cox

Dunlap

1994

The Journal of General Physiology

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“…The ratio of <i Ca > to <i Ba > with 40 mM external divalent cation was ∼1/3 ( Fig. 2D, black vs. red curves), as expected from prior single-channel studies (26,27). Reducing external Ca 2+ yielded progressively smaller currents (Fig.…”

Section: Significancesupporting

confidence: 83%

Ca ²⁺ channel nanodomains boost local Ca ²⁺ amplitude

Tadross

Tsien

Yue

2013

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

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Local Ca 2+ signals through voltage-gated Ca 2+ channels (Ca V s) drive synaptic transmission, neural plasticity, and cardiac contraction. Despite the importance of these events, the fundamental relationship between flux through a single Ca V channel and the Ca 2+ signaling concentration within nanometers of its pore has resisted empirical determination, owing to limitations in the spatial resolution and specificity of fluorescence-based Ca 2+ measurements. Here, we exploited Ca 2+ -dependent inactivation of Ca V channels as a nanometer-range Ca 2+ indicator specific to active channels. We observed an unexpected and dramatic boost in nanodomain Ca 2+ amplitude, ten-fold higher than predicted on theoretical grounds. Our results uncover a striking feature of Ca V nanodomains, as diffusion-restricted environments that amplify small Ca 2+ fluxes into enormous local Ca 2+ concentrations. This Ca 2+ tuning by the physical composition of the nanodomain may represent an energy-efficient means of local amplification that maximizes information signaling capacity, while minimizing global Ca 2+ load.L ocal Ca 2+ signals increase the information capacity of signaling within a cell, by enabling short-range signals to operate independently of Ca 2+ events elsewhere throughout the cell (1, 2). These local Ca 2+ signals are the conduit that drives diverse activity-dependent events, such as synaptic transmission (3), neural plasticity (4-6), and cardiac excitation-contraction coupling (7). However, with regard to the Ca 2+ amplitude within nanometers of individual Ca 2+ channels, our knowledge is based predominantly on diffusion theory, which predicts ∼100 μM Ca 2+ signals per picoampere flux at a distance of ∼10 nm from the pore (8-11). Although often quoted, this theory has been difficult to verify experimentally because diffusible Ca 2+ indicators report space-averaged [Ca 2+ ], and thus lack the spatial resolution needed for selective nanodomain reporting. Two recent efforts to overcome this limitation used voltage-gated Ca 2+ channel (Ca V )-tethered fluorescent Ca 2+ indicators to isolate nanodomain signals (12, 13), but were met with unexpected difficulties: Ca V -tethered indicators were unresponsive in the presence of high concentrations of intracellular 1,2-bis(oaminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), a Ca 2+ buffer that preserves Ca 2+ elevations within tens of nanometers of active channels but eliminates it elsewhere (8-10). A lack of response under these conditions would arise if the majority of tethered channels were silent, raising the concern that fluorescence changes observed under milder Ca 2+ buffering (12, 13) may represent the response of indicators tethered to silent channels, which nonetheless eavesdrop on Ca 2+ from active channels nearby. To overcome this fundamental limitation, we used a reverse strategy, whereby Ca 2+ /calmodulin-dependent inactivation (CDI) of channels themselves serves as a nanometer-range indicator of [Ca 2+ ]; a sensitive ionic readout that is unaffected by the pres...

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“…Similar results have been obtained using recombinant T-type (363) and native Ltype channels (161) and suggest that Ca 2ϩ binds with high affinity in the pore and permeates when displaced by a second Ca 2ϩ . A very interesting property of all voltagegated Ca 2ϩ channels is that they become highly permeable to Na ϩ in the absence of Ca 2ϩ .…”

Section: J Single-channel Recordingssupporting

confidence: 81%

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

1,518

1,446

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T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+ channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+ entry via T-type channels can directly regulate intracellular Ca2+ concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+ channels, and Na+ channels, indicating that they are evolutionarily related. Hence, the α1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.

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Calcium channel selectivity for divalent and monovalent cations. Voltage and concentration dependence of single channel current in ventricular heart cells.

Cited by 557 publications

References 42 publications

Inactivation of N-type calcium current in chick sensory neurons: calcium and voltage dependence.

Inactivation of N-type calcium current in chick sensory neurons: calcium and voltage dependence.

Ca ²⁺ channel nanodomains boost local Ca ²⁺ amplitude

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

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Calcium channel selectivity for divalent and monovalent cations. Voltage and concentration dependence of single channel current in ventricular heart cells.

Cited by 557 publications

References 42 publications

Inactivation of N-type calcium current in chick sensory neurons: calcium and voltage dependence.

Inactivation of N-type calcium current in chick sensory neurons: calcium and voltage dependence.

Ca 2+ channel nanodomains boost local Ca 2+ amplitude

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

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Ca ²⁺ channel nanodomains boost local Ca ²⁺ amplitude