Bilobal architecture is a requirement for calmodulin signaling to Ca
            <sub>V</sub>
            1.3 channels

Banerjee, Rahul; Yoder, Jesse; Yue, David T.; Amzel, L.M.; Tomaselli, Gordon F.; Gabelli, Sandra B.; Ben-Johny, Manu

doi:10.1073/pnas.1716381115

Cited by 22 publications

(22 citation statements)

References 90 publications

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“…The detailed analysis of the channel gating with Ca 2þ as a charge carrier is in agreement with a new model of L-type Ca V channel regulation by CaM and, thus, supports the interpretation that high-CDI states and high-P O states correspond to the identical CaM-bound state (27,50,51). In this model, simultaneous binding of both C-and N-lobes of apoCaM to the proximal C-terminus of Ca V 1.3 channels is required for the switching of the channel gating from the basal low to the high-P O mode.…”

Section: Mechanismsupporting

confidence: 84%

“…In our single-channel experiments, Ca V 1.3 42 channels spent $10% of the time in the high-P O state under basal conditions. Assuming 10% of all plasmalemmal Ca V 1.3 42 channels to hold CaM (i.e., to cause an about sevenfold higher peak current then the remaining 90% of the channels and to show a CDI value of $0.7 (27,37,50,51)), one calculates an apparent CDI of 0.3 for the whole ensemble of Ca V 1.3 42 channels. This agrees with the published values (27,33,37,38) explaining the only moderate inhibition of CDI by CTM in contrast to a nearly complete inhibition of CDI by CTM of Ca V 1.4 channels (32).…”

Section: Dynamic Competition Between Cam and Ctmmentioning

confidence: 99%

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Single-Channel Resolution of the Interaction between C-Terminal CaV1.3 Isoforms and Calmodulin

Kuzmenkina

Novikova

Jangsangthong

et al. 2019

Biophysical Journal

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Voltage-dependent calcium (Ca V ) 1.3 channels are involved in the control of cellular excitability and pacemaking in neuronal, cardiac, and sensory cells. Various proteins interact with the alternatively spliced channel C-terminus regulating gating of Ca V 1.3 channels. Binding of a regulatory calcium-binding protein calmodulin (CaM) to the proximal C-terminus leads to the boosting of channel activity and promotes calcium-dependent inactivation (CDI). The C-terminal modulator domain (CTM) of Ca V 1.3 channels can interfere with the CaM binding, thereby inhibiting channel activity and CDI. Here, we compared singlechannel gating behavior of two natural Ca V 1.3 splice isoforms: the long Ca V 1.3 42 with the full-length CTM and the short Ca V 1.3 42A with the C-terminus truncated before the CTM. We found that CaM regulation of Ca V 1.3 channels is dynamic on a minute timescale. We observed that at equilibrium, single Ca V 1.3 42 channels occasionally switched from low to high open probability, which perhaps reflects occasional binding of CaM despite the presence of CTM. Similarly, when the amount of the available CaM in the cell was reduced, the short Ca V 1.3 42A isoform showed patterns of the low channel activity. CDI also underwent periodic changes with corresponding kinetics in both isoforms. Our results suggest that the competition between CTM and CaM is influenced by calcium, allowing further fine-tuning of Ca V 1.3 channel activity for particular cellular needs.

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Section: Mechanismsupporting

confidence: 84%

Section: Dynamic Competition Between Cam and Ctmmentioning

confidence: 99%

Single-Channel Resolution of the Interaction between C-Terminal CaV1.3 Isoforms and Calmodulin

Kuzmenkina

Novikova

Jangsangthong

et al. 2019

Biophysical Journal

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“…In addition, quantifying CDI from single-channel currents (CDI SCH ) poses a more general sampling challenge that relates to the random nature of the CaM/channel interaction (42,43). This randomness renders uncertain whether in any one recording, sufficient on/off events are captured to recapitulate the full range of kinetic changes and thus to converge on the macroscopically observed CDI WC .…”

Section: Revealing CDI Of Single Nmda Receptor Currentsmentioning

confidence: 99%

Ca2+-Dependent Inactivation of GluN2A and GluN2B NMDA Receptors Occurs by a Common Kinetic Mechanism

Iacobucci

Popescu

2020

Biophysical Journal

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N-Methyl-d-aspartate (NMDA) receptors are Ca 2þ-permeable channels gated by glutamate and glycine that are essential for central excitatory transmission. Ca 2þ-dependent inactivation (CDI) is a regulatory feedback mechanism that reduces GluN2A-type NMDA receptor responses in an activity-dependent manner. Although CDI is mediated by calmodulin binding to the constitutive GluN1 subunit, prior studies suggest that GluN2B-type receptors are insensitive to CDI. We examined the mechanism of CDI subtype dependence using electrophysiological recordings of recombinant NMDA receptors expressed in HEK-293 cells. In physiological external Ca 2þ , we observed robust CDI of whole-cell GluN2A currents (0.42 5 0.05) but no CDI in GluN2B currents (0.08 5 0.07). In contrast, when Ca 2þ was supplied intracellularly, robust CDI occurred for both GluN2A and GluN2B currents (0.75 5 0.03 and 0.67 5 0.02, respectively). To examine how the source of Ca 2þ affects CDI, we recorded one-channel Na þ currents to quantify the receptor gating mechanism while simultaneously monitoring ionomycin-induced intracellular Ca 2þ elevations with fluorometry. We found that CDI of both GluN2A and GluN2B receptors reflects receptor accumulation in long-lived closed (desensitized) states, suggesting that the observed subtype-dependent differences in macroscopic CDI reflect intrinsic differences in equilibrium open probabilities (P o). We tested this hypothesis by measuring substantial macroscopic CDI, in physiologic conditions, for high P o GluN2B receptors (GluN1 A652Y /GluN2B). Together, these results show that Ca 2þ flux produces activity-dependent inactivation for both GluN2A and GluN2B receptors and that the extent of CDI varies with channel P o. These results are consistent with CDI as an autoinhibitory feedback mechanism against excessive Ca 2þ load during high P o activation.

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“…3) and is an essential property of calmodulin, which permits this protein to interact with a large and diverse array of partners. It has been recently demonstrated that calmodulin's bilobal architecture is essential for VGCC regulation (Banerjee et al 2018). The significant conformational changes on binding to its targets (Fallon et al 2005) can increase its affinity for Ca 2+ .…”

Section: Calmodulin the Physiology And Functions Of Calmodulinmentioning

confidence: 99%

Calcium Sensors in Neuronal Function and Dysfunction

Burgoyne

Helassa

McCue

et al. 2019

Cold Spring Harb Perspect Biol

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Calcium signaling in neurons as in other cell types can lead to varied changes in cellular function. Neuronal Ca 2+ signaling processes have also become adapted to modulate the function of specific pathways over a wide variety of time domains and these can have effects on, for example, axon outgrowth, neuronal survival, and changes in synaptic strength. Ca 2+ also plays a key role in synapses as the trigger for fast neurotransmitter release. Given its physiological importance, abnormalities in neuronal Ca 2+ signaling potentially underlie many different neurological and neurodegenerative diseases. The mechanisms by which changes in intracellular Ca 2+ concentration in neurons can bring about diverse responses is underpinned by the roles of ubiquitous or specialized neuronal Ca 2+ sensors. It has been established that synaptotagmins have key functions in neurotransmitter release, and, in addition to calmodulin, other families of EF-hand-containing neuronal Ca 2+ sensors, including the neuronal calcium sensor (NCS) and the calcium-binding protein (CaBP) families, play important physiological roles in neuronal Ca 2+ signaling. It has become increasingly apparent that these various Ca 2+ sensors may also be crucial for aspects of neuronal dysfunction and disease either indirectly or directly as a direct consequence of genetic variation or mutations. An understanding of the molecular basis for the regulation of the targets of the Ca 2+ sensors and the physiological roles of each protein in identified neurons may contribute to future approaches to the development of treatments for a variety of human neuronal disorders.C alcium signaling in many cell types can mediate a diverse range of changes in cellular function affecting gene expression, cell growth, development, survival, and cell death. In addition, neuronal calcium signaling processes have become adapted to modulate the function of other important pathways in the brain, including neuronal survival, axon outgrowth (Spitzer 2006), and changes in synaptic strength (Catterall and Few 2008;Catterall et al. 2013).Changes in the concentration of intracellular free Ca 2+ ([Ca 2+ ] i ) are essential for the transmission of information through the nervous system as the trigger for neurotransmitter release at synapses. In addition, alterations in [Ca 2+ ] i can lead to a wide variety of different physiological changes that can modify neuronal functions over a range of time domains of milliseconds through 10 sec, to minutes to days or longer (Berridge 1998). It has long been believed that

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Bilobal architecture is a requirement for calmodulin signaling to Ca _V 1.3 channels

Cited by 22 publications

References 90 publications

Single-Channel Resolution of the Interaction between C-Terminal CaV1.3 Isoforms and Calmodulin

Single-Channel Resolution of the Interaction between C-Terminal CaV1.3 Isoforms and Calmodulin

Ca2+-Dependent Inactivation of GluN2A and GluN2B NMDA Receptors Occurs by a Common Kinetic Mechanism

Calcium Sensors in Neuronal Function and Dysfunction

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Bilobal architecture is a requirement for calmodulin signaling to Ca V 1.3 channels

Cited by 22 publications

References 90 publications

Single-Channel Resolution of the Interaction between C-Terminal CaV1.3 Isoforms and Calmodulin

Single-Channel Resolution of the Interaction between C-Terminal CaV1.3 Isoforms and Calmodulin

Ca2+-Dependent Inactivation of GluN2A and GluN2B NMDA Receptors Occurs by a Common Kinetic Mechanism

Calcium Sensors in Neuronal Function and Dysfunction

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Product

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Bilobal architecture is a requirement for calmodulin signaling to Ca _V 1.3 channels