Similar Intracellular Ca<sup>2+</sup>Requirements for Inactivation and Facilitation of Voltage-Gated Ca<sup>2+</sup>Channels in a Glutamatergic Mammalian Nerve Terminal

Lin, Kun-Han; Erazo-Fischer, Emilio; Taschenberger, Holger

doi:10.1523/jneurosci.3838-11.2012

Cited by 18 publications

(11 citation statements)

References 60 publications

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“…The previous observation that CDI is only apparent in a fraction of cerebellar Purkinje neurons (Chaudhuri et al 2005) may coincide with this large EC 50 for CDI, and the sporadic attainment of these Ca 2+ levels. Interestingly, previous estimates of Ca 2+ sensitivity for CDF and CDI in the calyx of Held (EC 50 values of 2.5 μM and 6 μM, respectively; Lin et al 2012) are lower than the estimates provided here. This apparent discrepancy is most likely the result of differences in channel isoform expression.…”

Section: Advances In Functional Mechanismscontrasting

confidence: 94%

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Large Ca²⁺‐dependent facilitation of Ca_V2.1 channels revealed by Ca²⁺ photo‐uncaging

Lee

Adams

Yue

2015

The Journal of Physiology

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r These results suggest that Ca V 2.1 CDF would figure most prominently in short-term synaptic plasticity and cerebellar Purkinje cell rhythmicity.Abstract Ca V 2.1 (P-type) voltage-gated Ca 2+ channels constitute a major source of neuronal Ca 2+ current, strongly influencing rhythmicity and triggering neurotransmitter release throughout the central nervous system. Fitting with such stature among Ca 2+ entry pathways, Ca V 2.1 is itself feedback regulated by intracellular Ca 2+ , acting through calmodulin to facilitate channel opening. The precise neurophysiological role of this calcium-dependent facilitation (CDF) remains uncertain, however, in large measure because the very magnitude, Ca 2+ dependence and kinetics of CDF have resisted quantification by conventional means. Here, we utilize the photo-uncaging of Ca 2+ with Ca V 2.1 channels fluxing Li + currents, so that voltage-dependent activation of channel gating is no longer conflated with Ca 2+ entry, and CDF is then driven solely by light-induced increases in Ca 2+ . By using this strategy, we now find that CDF can be unexpectedly large, enhancing currents by as much as twofold at physiological voltages. CDF is steeply Ca 2+ dependent, with a Hill coefficient of approximately two, a half-maximal effect reached by nearly 500 nM Ca 2+ , and Ca 2+ on/off kinetics in the order of milliseconds to tens of milliseconds. These properties were established for both native P-type currents in cerebellar Purkinje neurons, as well as their recombinant channel counterparts under heterologous expression. Such features suggest that CDF of Ca V 2.1 channels may substantially enhance the regularity of rhythmic firing in cerebellar Purkinje neurons, where regularity is believed crucial for motor coordination. In addition, this degree of extensive CDF would be poised David T. Yue died on 23 December 2014.

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Section: Advances In Functional Mechanismscontrasting

confidence: 94%

“…Interestingly, previous estimates of Ca 2+ sensitivity for CDF and CDI in the calyx of Held (EC 50 values of 2.5 μ m and 6 μ m, respectively; Lin et al . ) are lower than the estimates provided here. This apparent discrepancy is most likely the result of differences in channel isoform expression.…”

Section: Discussioncontrasting

confidence: 77%

Large Ca²⁺‐dependent facilitation of Ca_V2.1 channels revealed by Ca²⁺ photo‐uncaging

Lee

Adams

Yue

2015

The Journal of Physiology

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“…Our findings may reconcile this low-flux high-fidelity paradox given that a single Ca V channel would, by virtue of nanodomain Ca 2+ boosting, have the potency of ∼10 channels in the absence of this amplification. Similar implications may apply to presynaptic physiology, where the Ca 2+ dependence of transmitter release has been experimentally determined (20,21,42,43), and the sensitivity to exogenous buffers (EGTA and BAPTA) has been characterized in several preparations (44,45). Whereas these findings are typically interpreted in the context of classical diffusion parameters, our findings may bear upon inferences of Ca V -vesicle distance and stoichiometry.…”

Section: Significancementioning

confidence: 53%

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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“…The time constants describing relaxation of I Ca facilitation (23 ms) and recovery from I Ca inactivation (110 ms) are comparable to those derived experimentally for P8–10 calyces (Lin et al . ).…”

Section: Discussionmentioning

confidence: 97%

Dynamics of volume‐averaged intracellular Ca²⁺ in a rat CNS nerve terminal during single and repetitive voltage‐clamp depolarizations

Lin

Taschenberger

Neher

2017

The Journal of Physiology

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Many aspects of short-term synaptic plasticity (STP) are controlled by relatively slow changes in the presynaptic intracellular concentration of free calcium ions ([Ca ] ) that occur in the time range of a few milliseconds to several seconds. In nerve terminals, [Ca ] equilibrates diffusionally during such slow changes, such that the globally measured, residual [Ca ] that persists after the collapse of local domains is often the appropriate parameter governing STP. Here, we study activity-dependent dynamic changes in global [Ca ] at the rat calyx of Held nerve terminal in acute brainstem slices using patch-clamp and microfluorimetry. We use low concentrations of a low-affinity Ca indicator dye (100 μm Fura-6F) in order not to overwhelm endogenous Ca buffers. We first study voltage-clamped terminals, dialysed with pipette solutions containing minimal amounts of Ca buffers, to determine Ca binding properties of endogenous fixed buffers as well as the mechanisms of Ca clearance. Subsequently, we use pipette solutions including 500 μm EGTA to determine the Ca binding kinetics of this chelator. We provide a formalism and parameters that allow us to predict [Ca ] changes in calyx nerve terminals in response to a wide range of stimulus protocols. Unexpectedly, the Ca affinity of EGTA under the conditions of our measurements was substantially lower (K = 543 ± 51 nm) than measured in vitro, mainly as a consequence of a higher than previously assumed dissociation rate constant (2.38 ± 0.20 s ), which we need to postulate in order to model the measured presynaptic [Ca ] transients.

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Similar Intracellular Ca²⁺Requirements for Inactivation and Facilitation of Voltage-Gated Ca²⁺Channels in a Glutamatergic Mammalian Nerve Terminal

Abstract: Voltage-gated Ca 2ϩ channels (VGCCs) of the P/Q-type, which are expressed at a majority of mammalian nerve terminals, show two types of Ca 2ϩ -dependent feedback regulation-inactivation (CDI) and facilitation (CDF

Cited by 18 publications

References 60 publications

Large Ca²⁺‐dependent facilitation of Ca_V2.1 channels revealed by Ca²⁺ photo‐uncaging

Large Ca²⁺‐dependent facilitation of Ca_V2.1 channels revealed by Ca²⁺ photo‐uncaging

Ca ²⁺ channel nanodomains boost local Ca ²⁺ amplitude

Dynamics of volume‐averaged intracellular Ca²⁺ in a rat CNS nerve terminal during single and repetitive voltage‐clamp depolarizations

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Similar Intracellular Ca2+Requirements for Inactivation and Facilitation of Voltage-Gated Ca2+Channels in a Glutamatergic Mammalian Nerve Terminal

Abstract: Voltage-gated Ca 2ϩ channels (VGCCs) of the P/Q-type, which are expressed at a majority of mammalian nerve terminals, show two types of Ca 2ϩ -dependent feedback regulation-inactivation (CDI) and facilitation (CDF

Cited by 18 publications

References 60 publications

Large Ca2+‐dependent facilitation of CaV2.1 channels revealed by Ca2+ photo‐uncaging

Large Ca2+‐dependent facilitation of CaV2.1 channels revealed by Ca2+ photo‐uncaging

Ca 2+ channel nanodomains boost local Ca 2+ amplitude

Dynamics of volume‐averaged intracellular Ca2+ in a rat CNS nerve terminal during single and repetitive voltage‐clamp depolarizations

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Similar Intracellular Ca²⁺Requirements for Inactivation and Facilitation of Voltage-Gated Ca²⁺Channels in a Glutamatergic Mammalian Nerve Terminal

Large Ca²⁺‐dependent facilitation of Ca_V2.1 channels revealed by Ca²⁺ photo‐uncaging

Large Ca²⁺‐dependent facilitation of Ca_V2.1 channels revealed by Ca²⁺ photo‐uncaging

Ca ²⁺ channel nanodomains boost local Ca ²⁺ amplitude

Dynamics of volume‐averaged intracellular Ca²⁺ in a rat CNS nerve terminal during single and repetitive voltage‐clamp depolarizations