Regulation of inositol 1,4,5-trisphosphate-induced Ca2+ release by reversible phosphorylation and dephosphorylation

AbstractThe inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is a universal intracellular Ca2+-release channel. It is activated after cell stimulation and plays a crucial role in the initiation and propagation of the complex spatio-temporal Ca2+ signals that control cellular processes as different as fertilization, cell division, cell migration, differentiation, metabolism, muscle contraction, secretion, neuronal processing, and ultimately cell death. To achieve these various functions, often in a single cell, exquisite control of the Ca2+ release is needed. This review aims to highlight how protein kinases and protein phosphatases can interact with the IP3R or with associated proteins and so provide a large potential for fine tuning the Ca2+-release activity and for creating efficient Ca2+ signals in subcellular microdomains

Symmetry Decomposition of Chaotic Dynamics

Discrete symmetries of dynamical flows give rise to relations between periodic orbits, reduce the dynamics to a fundamental domain, and lead to factorizations of zeta functions. These factorizations in turn reduce the labor and improve the convergence of cycle expansions for classical and quantum spectra associated with the flow. In this paper the general formalism is developed, with the $N$-disk pinball model used as a concrete example and a series of physically interesting cases worked out in detail.Comment: CYCLER Paper 93mar01

Five million years of compositionally diverse, episodic volcanism : construction of Davidson Seamount atop an abandoned spreading center

Davidson Seamount, a volcano located about 80 km off the central California coast, has a volume of ~320 km³ and consists of a series of parallel ridges serrated with steep cones. Davidson was sampled and its morphology observed during 27 ROV Tiburon dives. During those dives, 286 samples of lava, volcaniclastite, and erratics from the continental margin were collected, with additional samples from one ROV-collected push core and four gravity cores. We report glass compositions for 99 samples and ⁴⁰Ar-³⁹Ar incremental heating age data for 20 of the samples. The glass analyses are of hawaiite (62%), mugearite (13%), alkalic basalt (9%), and tephrite (8%), with minor transitional basalt (2%), benmoreite (2%), and trachyandesite (2%). The lithologies are irregularly distributed in space and time. The volcano erupted onto crust inferred to be 20 Ma from seafloor magnetic anomalies. Ages of the lavas range from 9.8 to 14.8 Ma. The oldest rocks are from the central ridge, and the youngest are from the flanks and southern end of the edifice. The compositions of the 18 reliably dated volcanic cones vary with age such that the oldest lavas are the most fractionated. The melts lost 65% to nearly 95% of their initial S because of bubble loss during vesiculation, and the shallowest samples have S contents similar to lava erupted subaerially in Hawaii. Despite this similarity in S contents, there is scant other evidence to suggest that Davidson was ever an island. The numerous small cones of disparate chemistry and the long eruptive period suggest episodic growth of the volcano over at least 5 Myr and perhaps as long as 10 Myr if it began to grow when the spreading ridge was abandoned

Role of IP3 Receptors during Early Zebrafish Development.

Fluctuations in cytosolic Ca2+ are crucial for a variety of cellular processes including many aspects of development. Mobilization of intracellular Ca2+ stores via the production of inositol trisphosphate (IP3) and the consequent activation of IP3-sensitive Ca2+ channels is a ubiquitous means by which diverse stimuli mediate their cellular effects. Although IP3 receptors have been well studied at fertilization, information regarding their possible involvement during subsequent development is scant. In the present study we examined the role of IP3 receptors in early development of the zebrafish. We report the first molecular analysis of zebrafish IP3 receptors which indicates that, like mammals, the zebrafish genome contains three distinct IP3 receptor genes. mRNA for all isoforms was detectable at differing levels by the 64 cell stage, and IP3-induced Ca2+ transients could be readily generated (by flash photolysis) in a controlled fashion throughout the cleavage period in vivo. Furthermore, we show that early blastula formation was disrupted by pharmacological blockade of IP3 receptors or phospholipase C, by molecular inhibition of the former by injection of IRBIT (IP3 receptor-binding protein released with IP3) and by depletion of thapsigargin-sensitive Ca2+ stores after completion of the second cell cycle. Inhibition of Ca2+ entry or ryanodine receptors, however, had little effect. Our work defines the importance of IP3 receptors during early development of a genetically and optically tractable model vertebrate organism

Unraveling the role of polycystin-2/inositol 1,4,5-trisphosphate receptor interaction in Ca2+ signaling

Autosomal dominant polycystic kidney disease (ADPKD) arises as a consequence of mutations of the genes PKD1 and PKD2, encoding respectively the integral membrane proteins polycystin-1 and polycystin-2 (TRPP2), resulting in a disturbance in intracellular Ca2+ signaling. Previously we investigated the interaction between TRPP2 and the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R), an intracellular Ca2+ channel in the endoplasmic reticulum (ER). We identified the molecular determinants of this interaction and observed an enhanced IP3-induced Ca2+ release (IICR). Since we found that TRPP2 strongly bound to a cluster of positively charged amino acids in the N-terminal ligand-binding domain (LBD) of the IP3R, we now investigated whether TRPP2 would interfere with the binding of IP3 to the IP3R. In in vitro experiments we observed that TRPP2 partially inhibited the binding of IP3 to the LBD of the IP3R with an IC50 of ~350 nM. The suppressor domain, i.e. the N-terminal 225 amino acids of the LBD of the IP3R, mediated this inhibitory effect of TRPP2 on IP3 binding. The observation that the interaction between the IP3R and TRPP2 decreased IP3 binding is in apparent contrast to the increased IICR. The data can be explained however by a subsequent activation of Ca2+-induced Ca2+ release (CICR) via TRPP2. Implications of this mechanism for cellular Ca2+ signaling are discussed in this addendum

Heterogeneous Nuclear Ribonucleoprotein H1, a Novel Nuclear Autoantigen

BACKGROUND: Serum samples from patients with autoimmune connective tissue diseases that show a finely speckled antinuclear antibody (ANA) on indirect immune-fluorescence often have antibodies against unknown nuclear target antigens. To search for such autoantigens we applied a proteomic approach using sera from patients with a high ANA titer (>= 640) and Finely speckled fluorescence but in whom no antibodies to extractable nuclear antigens (ENA) could be identified. METHODS: Using an immunoproteomics approach we identified heterogeneous nuclear ribonucleoprotein HI (hnRNP HI) as a novel nuclear target of autoantibody response. RESULTS: Recombinant rat hnRNP H I reacted in Western blot analyses with 48% of 93 sera from patients with primary Sjogren syndrome and with 5.2% of 153 sera from patients with other connective tissue diseases (diseased controls). For comparison, the diagnostic sensitivity and specificity of anti-Sjogren syndrome A (SSA) antibodies for primary Sjogren syndrome in the same patient cohort were 88.2% and 76.3%, respectively. Interestingly, 5 of 11 primary Sjogren syndrome patients with no anti-SSA or anti-SSB antibodies had anti-hnRNP HI antibodies. Anti-hnRNP H1 antibodies were preabsorbed by hnRNP H1, as demonstrated by indirect immunofluorescence. In an evaluation of the presence of anti-hnRNP H I antibodies in 188 consecutive samples submitted to the clinical laboratory with positive ANA (titer >= 160), anti-hnRNP H1 antibodies were found in 3 of 7 (2 primary and 5 secondary) Sjogren syndrome patients and in 8.3% of the diseased controls. CONCLUSIONS: HnRNP H1 is a newly discovered autoantigen that could become an additional diagnostic marker. (C) 2009 American Association for Clinical Chemistr