Sense and sensibility in the regulation of voltage-gated Ca2+ channels

doi:10.1016/S0166-2236(02)02247-6

Trends in Neurosciences

Volume 25, Issue 10, 1 October 2002, Pages 489-491

https://doi.org/10.1016/S0166-2236(02)02247-6 Get rights and content

Abstract

Voltage-gated Ca²⁺ channels are crucial for neurotransmitter release and other neuronal functions, and their activity-dependent regulation could underlie various aspects of synaptic plasticity. Recent studies have identified Ca²⁺-sensing proteins involved in Ca²⁺-channel modulation. These have complex effects on channel gating, and data suggest that the actions of multiple Ca²⁺ sensors are important for the fine-tuning of Ca²⁺ channel activity.

Section snippets

NCS proteins and Ca²⁺-channel regulation

NCS proteins, like calmodulin, are members of the superfamily of EF-hand Ca²⁺-binding proteins. Unlike calmodulin, the NCS proteins are found mainly in neurons, have a high affinity for Ca²⁺ (0.25–0.6 μm) and are N-terminally myristoylated 11., 12.. One of the NCS proteins, NCS-1, has established roles in the regulation of neurotransmission and in synaptic plasticity. NCS-1 was originally identified in Drosophila, in which the overexpression mutant (called frequenin) displays increased

Regulation by multiple Ca²⁺ sensors

A subfamily of CaBPs more closely related to calmodulin than to the NCS proteins [20] have also been implicated in the regulation of P/Q-type voltage-gated Ca²⁺ channels [21]. It was reported that CaBP1 binds to the calmodulin-binding (CDB) site of P/Q-type Ca²⁺ channels but has markedly different effects compared with calmodulin [21]. CaBP1 caused significantly faster inactivation of P/Q-type Ca²⁺ channels (Fig. 1b) and also shifted the voltage-activation curves for the channels in the

Unanswered questions

As our knowledge of modulators of voltage-gated Ca²⁺ channels has increased, so have the number of questions concerning their regulation by Ca²⁺ sensor proteins. How is it that calmodulin and NCS-1 can both inhibit and facilitate the very same P/Q-type channel? One possibility is that this relates to the expression of different forms of the auxiliary Ca²⁺-channel subunits that can affect regulation [22]. In addition, the calyx of Held does not appear to have the same type of GPCR inhibitory

Conclusions

Two certainties are that the identified Ca²⁺-sensing proteins have differential and complicated effects on voltage-gated Ca²⁺ channels, and that the observed modulatory effect depends on the pathway(s) active at a particular time, and possibly also on cell type. The tight control of neuronal function and quick adaptive responses require that a repertoire of Ca²⁺-sensing proteins is available for regulation of voltage-gated Ca²⁺ channels in response to varied transient Ca²⁺ signals. Further work

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Ca²⁺ signalling via the neuronal calcium sensor-1 regulates associative learning and memory in C.elegans
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NCS-1/frequenin functions in an autocrine pathway regulating Ca²⁺ channels in bovine adrenal chromaffin cells
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Voltage-independent inhibition of P/Q-type Ca²⁺ channels in adrenal chromaffin cells via a neuronal Ca²⁺ sensor-1-dependent pathway involves Src-family tyrosine kinase
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Ca²⁺ binding protein frequenin mediates GDNF-induced potentiation of Ca²⁺ channels and transmitter release
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Differential use of myristoyl groups on neuronal calcium sensor proteins as a determinant of spatio-temporal aspects of Ca ²⁺-signal transduction

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Ca²⁺-dependent inactivation of cloned cardiac Ca²⁺ channel α1 subunit (α1C) expressed in Xenopus oocytes

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Cited by (34)

Conformational Selection in a Protein-Protein Interaction Revealed by Dynamic Pathway Analysis
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Citation Excerpt :
Here, we combine both structural identification of the pre-existing conformations and kinetic measurements of flux for binding of rhodopsin kinase to its regulator recoverin to unambiguously identify the pathway of protein complex formation. Recoverin is a 23 kDa Ca2+-binding protein that belongs to the neuronal calcium sensing (NCS) family (Burgoyne and Weiss, 2001; Weiss and Burgoyne, 2002). Recoverin inhibits rhodopsin kinase, a serine/threonine kinase responsible for termination of the photo-activated state of rhodopsin in rod photoreceptor cells (Chen et al., 1995; Klenchin et al., 1995).
Molecular recognition plays a central role in biology, and protein dynamics has been acknowledged to be important in this process. However, it is highly debated whether conformational changes happen before ligand binding to produce a binding-competent state (conformational selection) or are caused in response to ligand binding (induced fit). Proposals for both mechanisms in protein/protein recognition have been primarily based on structural arguments. However, the distinction between them is a question of the probabilities of going via these two opposing pathways. Here, we present a direct demonstration of exclusive conformational selection in protein/protein recognition by measuring the flux for rhodopsin kinase binding to its regulator recoverin, an important molecular recognition in the vision system. Using nuclear magnetic resonance (NMR) spectroscopy, stopped-flow kinetics, and isothermal titration calorimetry, we show that recoverin populates a minor conformation in solution that exposes a hydrophobic binding pocket responsible for binding rhodopsin kinase. Protein dynamics in free recoverin limits the overall rate of binding.
Acid-sensing ion channel 2 (ASIC2) in the intestine of adult zebrafish
2011, Neuroscience Letters
Acid-sensing ion channels (ASICs) in mammals monitor acid sensing and mechanoreception. They have a widespread expression in the central and peripheral nervous system, including the gut. The distribution of ASICs in zebrafish is known only in larvae and at the mRNA level. Here we have investigated the expression and cell distribution of ASIC2 in the gut of adult zebrafish using PCR, Western blot and immunohistochemistry. ASIC2 mRNA was detected in the gut, and a protein consistent with predicted ASIC2 (64 kDa molecular mass) was detected by Western blot. ASIC2 positivity was found in a subpopulation of myenteric neurons in the enteric nervous system, as well in enteroendocrine epithelial cells. These data demonstrate for the first time the occurrence of ASIC2 in the gut of adult zebrafish where it presumably acts as a chemosensor and a mechanosensor.
Structural basis for the differential effects of CaBP1 and calmodulin on Ca<inf>V</inf>1.2 calcium-dependent inactivation
2010, Structure
Citation Excerpt :
These effects depend on displacement of CaM from the CaVα1 C-terminal IQ domain (Yang et al., 2006; Zhou et al., 2004), a channel element that is critical for CaM-mediated CDI (Erickson et al., 2003; Zühlke et al., 1999). As with many calcium-sensor proteins (Burgoyne et al., 2004; Haeseleer et al., 2002; Weiss and Burgoyne, 2002), both CaBP1 and CaM comprise two lobes that bear a pair of EF-hand calcium-binding motifs (Haeseleer et al., 2000). Beyond this common architecture, there are a number of differences.
Calcium-binding protein 1 (CaBP1), a calmodulin (CaM) homolog, endows certain voltage-gated calcium channels (Ca_Vs) with unusual properties. CaBP1 inhibits Ca_V1.2 calcium-dependent inactivation (CDI) and introduces calcium-dependent facilitation (CDF). Here, we show that the ability of CaBP1 to inhibit Ca_V1.2 CDI and induce CDF arises from interaction between the CaBP1 N-lobe and interlobe linker residue Glu94. Unlike CaM, where functional EF hands are essential for channel modulation, CDI inhibition does not require functional CaBP1 EF hands. Furthermore, CaBP1-mediated CDF has different molecular requirements than CaM-mediated CDF. Overall, the data show that CaBP1 comprises two structural modules having separate functions: similar to CaM, the CaBP1 C-lobe serves as a high-affinity anchor that binds the Ca_V1.2 IQ domain at a site that overlaps with the Ca²⁺/CaM C-lobe site, whereas the N-lobe/linker module houses the elements required for channel modulation. Discovery of this division provides the framework for understanding how CaBP1 regulates Ca_Vs.
Neuronal calcium sensor proteins are unable to modulate NFAT activation in mammalian cells
2008, Biochimica et Biophysica Acta - General Subjects
Calcium activated gene transcription through Nuclear Factor of Activated T-cells, (NFAT) proteins, is emerging as a ubiquitous mechanism for the control of important physiological processes. Of the five mammalian NFAT isoforms, transcriptional activities of NFATs 1-4 are stimulated by a calcium driven association between the ubiquitous phosphatase calcineurin and the calcium-sensing protein calmodulin. Published in vitro evidence has suggested that other members of the calmodulin super-family, in particular the neuronal calcium sensor (NCS) proteins, can similarly modulate calcineurin activity. In this study we have assessed the ability of NCS proteins to interact directly with calcineurin in vitro and report a specific if weak association between various NCS proteins and the phosphatase. In an extension to these analyses we have also examined the effects of over-expression of NCS-1 or NCS-1 mutants on calcineurin signalling in HeLa cells in experiments examining the dephosphorylation of an NFAT-GFP reporter construct as a readout of calcineurin activity. Results from these experiments indicate that NCS-1 was not able to detectably modulate calcineurin/NFAT signalling in a live mammalian cell system, findings that are consistent with the idea that calmodulin and not NCS-1 or other NCS family proteins is the physiologically relevant modulator of calcineurin activity.
Molecular mechanism for divergent regulation of Ca<inf>v</inf>1.2 Ca 2+ channels by calmodulin and Ca2+-binding protein-1
2005, Journal of Biological Chemistry
Citation Excerpt :
These findings provide an initial framework for understanding the molecular coupling between a growing number of Ca2+-binding proteins and voltage-gated Ca2+ channels (44, 45) and the diverse functional consequences of such interactions.
Ca²⁺-binding protein-1 (CaBP1) and calmodulin (CaM) are highly related Ca²⁺-binding proteins that directly interact with, and yet differentially regulate, voltage-gated Ca²⁺ channels. Whereas CaM enhances inactivation of Ca²⁺ currents through Ca_v1.2 (L-type) Ca²⁺ channels, CaBP1 completely prevents this process. How CaBP1 and CaM mediate such opposing effects on Ca_v1.2 inactivation is unknown. Here, we identified molecular determinants in the α₁-subunit of Ca_v1.2 (α₁1.2) that distinguish the effects of CaBP1 and CaM on inactivation. Although both proteins bind to a well characterized IQ-domain in the cytoplasmic C-terminal domain of α₁1.2, mutations of the IQ-domain that significantly weakened CaM and CaBP1 binding abolished the functional effects of CaM, but not CaBP1. Pulldown binding assays revealed Ca²⁺-independent binding of CaBP1 to the N-terminal domain (NT) of α₁1.2, which was in contrast to Ca²⁺-dependent binding of CaM to this region. Deletion of the NT abolished the effects of CaBP1 in prolonging Ca_v1.2 Ca²⁺ currents, but spared Ca²⁺-dependent inactivation due to CaM. We conclude that the NT and IQ-domains of α₁1.2 mediate functionally distinct interactions with CaBP1 and CaM that promote conformational alterations that either stabilize or inhibit inactivation of Ca_v1.2.
Hypoxia sensing and pathways of cytosolic Ca2+ increases
2004, Cell Calcium
Oxygen-sensing and reactivity to changes in the concentration of oxygen is a fundamental property of cellular physiology. This central role is determined, mainly, by, to the fact that oxygen represents the final acceptor of electrons, derived from the normal cellular metabolism, at the end of the mitochondrial respiratory chain. Despite significant advances in molecular characterization of various oxygen-sensitive processes, the nature of the oxygen-sensor molecules and the mechanisms that link sensors to effects remains unclear. One such controversy is about the role and nature of reactive oxygen species (ROS) changes during hypoxia. Irrespective of the mechanisms of oxygen sensing, one of the constant early responses to hypoxia in almost all cell types is an increase in intracellular Ca²⁺ ([Ca²⁺]_i). In many instances, this increase is mediated by the activation of various plasma membrane Ca²⁺ conductances. Some of these channels have specific Ca²⁺ permeability (e.g. voltage-operated Ca²⁺ channels), whereas others have non-specific cation conductances and are activated by a variety of ligands (ligand-operated channels). In the last decade, a large superfamily of channels with significant Ca²⁺ permeability has been progressively identified and characterised: the TRP channels. Through their properties, some groups of the TRP channels provide a link to the other hypoxia-activated mechanism of [Ca²⁺]_i increase: the release of Ca²⁺ from intracellular Ca²⁺ stores. Since the [Ca²⁺]_i signals, depending on their localization and intensity, are important regulators of the subsequent cellular responses to hypoxia, a deeper understanding of the mechanisms through which hypoxia regulate the activity of these pathways that increase intracellular Ca²⁺ could point the way towards the development of new therapeutic approaches to reduce or suppress the pathological effects of cellular hypoxia, such as those seen in stroke or myocardial ischemia.

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Trends in Neurosciences

Abstract

Section snippets

NCS proteins and Ca²⁺-channel regulation

Regulation by multiple Ca²⁺ sensors

Unanswered questions

Conclusions

References (25)

Calmodulin is the Ca²⁺ sensor for Ca²⁺-dependent inactivation of L-type calcium channels

Neuron

Preassociation of calmodulin with voltage-gated Ca²⁺ channels revealed by FRET in single living cells

Neuron

Receptor-mediated pathways that modulate calcium channels

Semin. Neurosci.

Frequenin-A novel calcium-binding protein that modulates synaptic efficacy in the Drosophila nervous system

Neuron

NCS-1, the mammalian homologue of frequenin is expressed in chromaffin and PC12 cells and regulates neurosecretion from dense-core granules

J. Biol. Chem.

Ca²⁺ signalling via the neuronal calcium sensor-1 regulates associative learning and memory in C.elegans

Neuron

NCS-1/frequenin functions in an autocrine pathway regulating Ca²⁺ channels in bovine adrenal chromaffin cells

J. Biol. Chem.

Voltage-independent inhibition of P/Q-type Ca²⁺ channels in adrenal chromaffin cells via a neuronal Ca²⁺ sensor-1-dependent pathway involves Src-family tyrosine kinase

J. Biol. Chem.

Ca²⁺ binding protein frequenin mediates GDNF-induced potentiation of Ca²⁺ channels and transmitter release

Neuron

Five members of a novel Ca²⁺ binding protein (CABP) subfamily with similarity to calmodulin

J. Biol. Chem.

Differential use of myristoyl groups on neuronal calcium sensor proteins as a determinant of spatio-temporal aspects of Ca ²⁺-signal transduction

J. Biol. Chem.

Ca²⁺-dependent inactivation of cloned cardiac Ca²⁺ channel α1 subunit (α1C) expressed in Xenopus oocytes

Biophys. J.

Cited by (34)

Conformational Selection in a Protein-Protein Interaction Revealed by Dynamic Pathway Analysis

Acid-sensing ion channel 2 (ASIC2) in the intestine of adult zebrafish

Structural basis for the differential effects of CaBP1 and calmodulin on Ca<inf>V</inf>1.2 calcium-dependent inactivation

Neuronal calcium sensor proteins are unable to modulate NFAT activation in mammalian cells

Molecular mechanism for divergent regulation of Ca<inf>v</inf>1.2 Ca <sup>2+</sup> channels by calmodulin and Ca<sup>2+</sup>-binding protein-1

Hypoxia sensing and pathways of cytosolic Ca<sup>2+</sup> increases

Trends in Neurosciences

Research updateSense and sensibility in the regulation of voltage-gated Ca2+ channels

Abstract

Section snippets

NCS proteins and Ca2+-channel regulation

Regulation by multiple Ca2+ sensors

Unanswered questions

Conclusions

Neuron

Neuron

Semin. Neurosci.

Neuron

J. Biol. Chem.

Neuron

J. Biol. Chem.

J. Biol. Chem.

Neuron

J. Biol. Chem.

J. Biol. Chem.

Biophys. J.

Research update
Sense and sensibility in the regulation of voltage-gated Ca²⁺ channels

NCS proteins and Ca²⁺-channel regulation

Regulation by multiple Ca²⁺ sensors