Endogenous and Exogenous Ca2+ Buffers Differentially Modulate Ca2+-dependent Inactivation of CaV2.1 Ca2+ Channels

Kreiner, Lisa; Lee, Amy

doi:10.1074/jbc.m511971200

Cited by 32 publications

(31 citation statements)

References 62 publications

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“…However, we saw no difference in the instantaneous current, or the fully facilitated current, when using either 1 or 10 mM intracellular EGTA, whereas most studies on voltage-gated calcium channels or neurotransmitter release processes find 10 mM intracellular EGTA to be as efficient as 5 mM BAPTA (Kits and Mansvelder, 2000). The most likely explanation is that the massive calcium entry associated with the large (several nanoamperes), non-desensitizing P2X 7 R current over many seconds rapidly saturates EGTA at Ͻ20 mM, as has been found for synaptic transmission at the squid giant synapse (Adler et al, 1991) and for calcium-dependent inactivation of voltage-gated calcium channels by several endogenous calcium buffering proteins (Kreiner and Lee, 2006). It has also been shown that mitochondrial stores of Ca 2ϩ are released in the millisecond to second time domain on P2X 7 R stimulation Mackenzie et al, 2005), thus providing an additional calcium surge that may be expected to saturate these buffers.…”

Section: Discussionmentioning

confidence: 92%

Facilitation of P2X7 Receptor Currents and Membrane Blebbing via Constitutive and Dynamic Calmodulin Binding

Roger¹,

Pelegrı́n²,

Surprenant³

2008

Journal of Neuroscience

111

110

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The ATP-gated P2X 7 receptor (P2X 7 R) is a highly unusual calcium-permeable cationic channel in that within seconds of its activation, dramatic and reversible cytoskeletal rearrangements with prominent membrane blebbing occurs. Agonist-induced membrane currents at hyperpolarized potentials show pronounced facilitation during the initial 30 -100 s of receptor activation but mechanisms responsible have not been elucidated. We measured facilitation of ATP-gated currents in HEK cells expressing rat P2X 7 R and delineated distinct calcium-dependent and independent processes. The calcium-dependent facilitation was composed of an instantaneous (millisecond time domain) and slowly developing (time constant, 20 s with maximum agonist stimulation) component. Both components were prevented when recording with a highly specific calmodulin (CaM) inhibitory peptide but only the instantaneous component was reduced by expression of the dominant-negative EF-handless CaM mutant. Coimmunoprecipitation assays detected low levels of CaM binding to unstimulated P2X 7 R, and this increased by 50% during 45 s stimulation of the receptor. We identified a novel 1-5-16 Ca 2ϩ -dependent CaM binding motif in the intracellular C terminus of P2X 7 R; mutations in this domain resulted in the absence of calcium-dependent facilitation and binding of CaM to unstimulated or stimulated receptor. Blockade of CaM binding also delayed membrane blebbing by threefold. Our results demonstrate that CaM binds constitutively to closed P2X 7 R channels and dynamically during channel activation to significantly enhance and prolong calcium entry. This is the first example of CaM deregulating, rather than tightly controlling, calcium entry through an ion channel.

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Section: Discussionmentioning

confidence: 92%

Facilitation of P2X7 Receptor Currents and Membrane Blebbing via Constitutive and Dynamic Calmodulin Binding

Roger¹,

Pelegrı́n²,

Surprenant³

2008

Journal of Neuroscience

111

110

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“…These channels are regulated by Ca 2þ -dependent feedback mechanisms consisting of both Ca 2þ -dependent facilitation (CDF) and inactivation (CDI). While the former process is essentially mediated by the Ca 2þ sensor calmodulin (CaM) (Lee et al 2000a), CDI is modulated by synthetic Ca 2þ buffers (EGTA, BAPTA) and by the Ca 2þ buffers PV and CB-D28k in vitro (Kreiner and Lee 2005). Of note, PV and CB-D28k affect Ca v 2.1 channel function differently than the synthetic buffers EGTA and BAPTA, often presumed to serve as close substitutes for endogenous Ca 2þ buffers.…”

Section: The Ca 2þ Homeostasomementioning

confidence: 99%

Cytosolic Ca2+ Buffers

Schwaller¹

2010

Cold Spring Harbor Perspectives in Biology

348

305

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“…Multicompartment distribution of free Ca 2 þ hypothesized in the brain in vivo during the baseline conditions (A-C) and evoked neural activity conditions (D-F) based on in vitro literature on Ca 2 þ measurements from neurons, glia, and brain slices. 2,4,5,7,8,[13][14][15][16][17][18][19][20][21][22][23][24][25] (D) During normal physiologic conditions, evoked brain activity can decrease extracellular and endoplasmic reticular Ca 2 þ ranges, and increase cytoplasmic and mitochondria Ca 2 þ ranges. (E) During mCU inhibition, evoked activity can lead to a relatively smaller decrease in extracellular and endoplasmic reticular (ER) Ca 2 þ ranges and smaller increase in cytoplasmic and mitochondrial Ca 2 þ ranges.…”

Section: Surgical Preparationmentioning

confidence: 99%

“…From in vitro studies of Ca 2 þ in slices and various cell types of the central nervous system, 2,4,5,7,8,[13][14][15][16][17][18][19][20][21][22][23][24][25] we evaluated spontaneous and evoked activity state-dependent Ca 2 þ ranges in multiple compartments in vivo consisting of the extracellular space as well as microdomains of cytoplasm and mitochondria ( Figure 1). We hypothesized that diminished mCU activity signifying deficient mitochondrial function via decreased Ca 2 þ cycling will decrease mitochondrial Ca 2 þ with unchanged to minimally decreased overall cytoplasmic Ca 2 þ (overall ¼ cytoplasmic þ microdomains) ( Figures 1B and 1E), leading to reduced oxidative metabolism, electrical activity, and hemodynamic response.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Calcium Uptake Capacity Modulates Neocortical Excitability

Sanganahalli

Hermán

Hyder

et al. 2013

J Cereb Blood Flow Metab

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Local calcium (Ca 2 þ ) changes regulate central nervous system metabolism and communication integrated by subcellular processes including mitochondrial Ca 2 þ uptake. Mitochondria take up Ca 2 þ through the calcium uniporter (mCU) aided by cytoplasmic microdomains of high Ca 2 þ . Known only in vitro, the in vivo impact of mCU activity may reveal Ca 2 þ -mediated roles of mitochondria in brain signaling and metabolism. From in vitro studies of mitochondrial Ca 2 þ sequestration and cycling in various cell types of the central nervous system, we evaluated ranges of spontaneous and activity-induced Ca 2 þ distributions in multiple subcellular compartments in vivo. We hypothesized that inhibiting (or enhancing) mCU activity would attenuate (or augment) cortical neuronal activity as well as activity-induced hemodynamic responses in an overall cytoplasmic and mitochondrial Ca 2 þ -dependent manner. Spontaneous and sensory-evoked cortical activities were measured by extracellular electrophysiology complemented with dynamic mapping of blood oxygen level dependence and cerebral blood flow. Calcium uniporter activity was inhibited and enhanced pharmacologically, and its impact on the multimodal measures were analyzed in an integrated manner. Ru360, an mCU inhibitor, reduced all stimulus-evoked responses, whereas Kaempferol, an mCU enhancer, augmented all evoked responses. Collectively, the results confirm aforementioned hypotheses and support the Ca 2 þ uptake-mediated integrative role of in vivo mitochondria on neocortical activity.

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Endogenous and Exogenous Ca2+ Buffers Differentially Modulate Ca2+-dependent Inactivation of CaV2.1 Ca2+ Channels

Cited by 32 publications

References 62 publications

Facilitation of P2X7 Receptor Currents and Membrane Blebbing via Constitutive and Dynamic Calmodulin Binding

Facilitation of P2X7 Receptor Currents and Membrane Blebbing via Constitutive and Dynamic Calmodulin Binding

Cytosolic Ca2+ Buffers

Mitochondrial Calcium Uptake Capacity Modulates Neocortical Excitability

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