Neuronal Ca2+-sensor proteins: multitalented regulators of neuronal function

Burgoyne, Robert D.; O'Callaghan, Dermott W.; Hasdemir, Burcu; Haynes, Lee P.; Tepikin, Alexei V.

doi:10.1016/j.tins.2004.01.010

Cited by 189 publications

(154 citation statements)

References 74 publications

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“…This is particularly evident for the loop connecting the N-and C-terminal domains (region III), which is well-ordered in the wild-type protein. In contrast, the corresponding portion in the mutant not only adopts a different conformation, but also exhibits strongly enhanced mobility, indicated by large B factors 4 and very weak electron density. For a plot of main chain B factors per residue (normalized to the mean B value of all main chain atoms) please refer to Fig.…”

Section: Resultsmentioning

confidence: 96%

“…NCS proteins are grouped into five subfamilies and show a rather heterogeneous localization and function in the nervous system (4). In the photoreceptor cells of the vertebrate retina, for instance, recoverin and several isoforms of guanylate cyclase activating protein (GCAP) detect changes in Ca 2ϩ concentration during or after illumination and regulate their target proteins in Ca 2ϩ -dependent feedback loops (5).…”

Section: Recoverin Is a Camentioning

confidence: 99%

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Tuning of a Neuronal Calcium Sensor

Weiergräber

Senin

Zernii

et al. 2006

Journal of Biological Chemistry

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Recoverin is a Ca2؉ -regulated signal transduction modulator expressed in the vertebrate retina that has been implicated in visual adaptation. An intriguing feature of recoverin is a cluster of charged residues at its C terminus, the functional significance of which is largely unclear. To elucidate the impact of this segment on recoverin structure and function, we have investigated a mutant lacking the C-terminal 12 amino acids. Whereas in myristoylated recoverin the truncation causes an overall decrease in Ca 2؉ sensitivity, results for the non-myristoylated mutant indicate that the truncation primarily affects the high affinity EF-hand 3. The three-dimensional structure of the mutant has been determined by x-ray crystallography. In addition to significant changes in average coordinates compared with wild-type recoverin, the structure provides strong indication of increased conformational flexibility, particularly in the C-terminal domain. Based on these observations, we propose a novel role of the C-terminal segment of recoverin as an internal modulator of Ca 2؉ sensitivity.Many biological processes are triggered or regulated by transient intracellular Ca 2ϩ signals. Because these signals elicit specific cellular responses, the precise detection of changes in cytoplasmic Ca 2ϩ concentration is a crucial step in many signaling pathways and requires sensing of Ca 2ϩ within very different concentration ranges. Ca 2ϩ -binding proteins work as intracellular Ca 2ϩ sensors and regulate their targets with high specificity and high spatial and temporal resolution. To achieve these remarkable tasks, Ca 2ϩ is recognized by specific amino acid sequence motifs, for example the C 2 domain and the EF-hand motif (1, 2). These motifs can detect subtle changes in Ca 2ϩ concentration and allow a fine tuning of Ca 2ϩ signaling. However, it remains a challenging problem to understand at a structural level how minimal changes in cytoplasmic Ca 2ϩ are reliably detected.The EF-hand superfamily of Ca 2ϩ -binding proteins includes, among others, the family of neuronal calcium sensor (NCS) 3 proteins (3), which are named because of their predominant expression in neuronal tissue. NCS proteins are grouped into five subfamilies and show a rather heterogeneous localization and function in the nervous system (4). In the photoreceptor cells of the vertebrate retina, for instance, recoverin and several isoforms of guanylate cyclase activating protein (GCAP) detect changes in Ca 2ϩ concentration during or after illumination and regulate their target proteins in Ca 2ϩ -dependent feedback loops (5).Recoverin inhibits rhodopsin kinase at high cytoplasmic Ca 2ϩ concentration (6 -9), a process that is thought to contribute to light adaptation of photoreceptor cells (9, 10). Recoverin harbors a myristoyl group at its N terminus (11), which is buried in a hydrophobic cleft in the Ca 2ϩ -free state (12). Upon Ca 2ϩ binding to the two functional EF-hands (EF-hand 2 and EFhand 3) (13) the acyl chain is exposed to the solvent. This socalled Ca 2ϩ -myrist...

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Section: Resultsmentioning

confidence: 96%

Section: Recoverin Is a Camentioning

confidence: 99%

Tuning of a Neuronal Calcium Sensor

Weiergräber

Senin

Zernii

et al. 2006

Journal of Biological Chemistry

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“…The NCS family, a group of EF-hand-containing proteins, plays a variety of roles in cell signaling (44), including regulation of ion channel function (4), activation of multiple target proteins such as kinases (6), and interactions with nucleic acids and control of cyclic nucleotide levels (5,19). In this study, we investigated VILIP-1 expression and its biological function in pancreatic ␤-cells.…”

Section: Discussionmentioning

confidence: 99%

The Neuronal Ca2+ Sensor Protein Visinin-like Protein-1 Is Expressed in Pancreatic Islets and Regulates Insulin Secretion

Dai

Zhang

Kang

et al. 2006

Journal of Biological Chemistry

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Visinin-like protein-1 (VILIP-1) is a member of the neuronal Ca 2؉ sensor protein family that modulates Ca 2؉-dependent cell signaling events. VILIP-1, which is expressed primarily in the brain, increases cAMP formation in neural cells by modulating adenylyl cyclase, but its functional role in other tissues remains largely unknown. In this study, we demonstrate that VILIP-1 is expressed in murine pancreatic islets and ␤-cells. To gain insight into the functions of VILIP-1 in ␤-cells, we used both overexpression and small interfering RNA knockdown strategies. Overexpression of VILIP-1 in the MIN6 ␤-cell line or isolated mouse islets had no effect on basal insulin secretion but significantly increased glucose-stimulated insulin secretion. cAMP accumulation was elevated in VILIP-1-overexpressing cells, and the protein kinase A inhibitor H-89 attenuated increased glucose-stimulated insulin secretion. Overexpression of VILIP-1 in isolated mouse ␤-cells increased cAMP content accompanied by increased cAMP-responsive element-binding protein gene expression and enhanced exocytosis as detected by cell capacitance measurements. Conversely, VILIP-1 knockdown by small interfering RNA caused a reduction in cAMP accumulation and produced a dramatic increase in preproinsulin mRNA, basal insulin secretion, and total cellular insulin content. The increase in preproinsulin mRNA in these cells was attributed to enhanced insulin gene transcription. Taken together, we have shown that VILIP-1 is expressed in pancreatic ␤-cells and modulates insulin secretion. Increased VILIP-1 enhanced insulin secretion in a cAMP-associated manner. Downregulation of VILIP-1 was accompanied by decreased cAMP accumulation but increased insulin gene transcription.

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“…Differential regulation of Ca V 2.1 channels by nCaBPs and synaptic plasticity nCaBPs that undergo large conformational changes after binding Ca 2ϩ Burgoyne et al, 2004) and bind Ca 2ϩ with submicromolar affinities ) are poised to act as potent regulators of synaptic transmission. nCaBPs may modulate synaptic responses by acting as local buffers that regulate residual Ca 2ϩ that accumulates with multiple action potentials (Zucker, 2003).…”

Section: Control Of Cabp1 and Vilip-2 Function By N-terminal Myristoymentioning

confidence: 99%

Differential Regulation of Ca_V2.1 Channels by Calcium-Binding Protein 1 and Visinin-Like Protein-2 Requires N-Terminal Myristoylation

Few¹,

Lautermilch²,

Westenbroek³

et al. 2005

J. Neurosci.

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2ϩ -independent manner. Block of myristoylation abolished these effects, leaving regulation that is similar to endogenous CaM. CaBP1/G2A binds to Ca V 2.1 with reduced stability, but in situ protein cross-linking and immunocytochemical studies revealed that it binds Ca V 2.1 in situ and is localized to the plasma membrane by coexpression with Ca V 2.1, indicating that it binds effectively in intact cells. In contrast to CaBP1, coexpression of VILIP-2 slows inactivation in a Ca 2ϩ -independent manner, but this effect also requires myristoylation. These results suggest a model in which nonmyristoylated CaBP1 and VILIP-2 bind to Ca V 2.1 channels and regulate them like CaM, whereas myristoylation allows differential, Ca 2ϩ -independent regulation by the inactive EF-hands of CaBP1 and VILIP-2, which differ in their positions in the protein structure. Differential, myristoylation-dependent regulation of presynaptic Ca 2ϩ channels by nCaBPs may provide a flexible mechanism for diverse forms of short-term synaptic plasticity.

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Neuronal Ca2+-sensor proteins: multitalented regulators of neuronal function

Cited by 189 publications

References 74 publications

Tuning of a Neuronal Calcium Sensor

Tuning of a Neuronal Calcium Sensor

The Neuronal Ca2+ Sensor Protein Visinin-like Protein-1 Is Expressed in Pancreatic Islets and Regulates Insulin Secretion

Differential Regulation of Ca_V2.1 Channels by Calcium-Binding Protein 1 and Visinin-Like Protein-2 Requires N-Terminal Myristoylation

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Neuronal Ca2+-sensor proteins: multitalented regulators of neuronal function

Cited by 189 publications

References 74 publications

Tuning of a Neuronal Calcium Sensor

Tuning of a Neuronal Calcium Sensor

The Neuronal Ca2+ Sensor Protein Visinin-like Protein-1 Is Expressed in Pancreatic Islets and Regulates Insulin Secretion

Differential Regulation of CaV2.1 Channels by Calcium-Binding Protein 1 and Visinin-Like Protein-2 Requires N-Terminal Myristoylation

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Differential Regulation of Ca_V2.1 Channels by Calcium-Binding Protein 1 and Visinin-Like Protein-2 Requires N-Terminal Myristoylation