ERK activation by Ca2+ ionophores depends on Ca2+ entry in lymphocytes but not in platelets, and does not conduct membrane scrambling

Rapid Ca²⁺-dependent phospholipid (PL) reorganization (scrambling) at the plasma membrane is a mechanism common to hematopoietic cells exposing procoagulant phosphatidylserine (PS). The aim of this research was to determine whether activation of the extracellular signal-regulated kinase (ERK) pathway was required for PL scrambling, based on a single report analyzing both responses induced by Ca²⁺ ionophores in megakaryoblastic HEL cells. Ca²⁺ ionophore-stimulated ERK phosphorylation was induced in platelets without external Ca²⁺, whereas exogenous Ca²⁺ entry was crucial for ERK activation in Jurkat T cells. In both cells, membrane scrambling only occurred following Ca²⁺ entry and was not blocked by inhibiting ERK phosphorylation. Furthermore, ERK proteins are strongly phosphorylated in transformed B lymphoblastic cell lines, which do not expose PS in their resting state. Overall, the data demonstrated that ERK activation and membrane scrambling are independent mechanisms. A. Arachiche, I. Badirou: These authors contributed equally to this work. Received 18 June 2008; received after revision 24 September 2008; accepted 1 October 2008     

Olfactory receptor trafficking to the plasma membrane

Olfactory receptors typically exhibit poor plasma membrane localization and functionality when heterologously expressed in most cell types. It has therefore proven difficult to effectively study olfactory receptor pharmacology and signaling mechanisms using traditional cell culture systems. Over the past few years, a variety of distinct proteins have been reported to interact with olfactory receptors and facilitate olfactory receptor trafficking to the plasma membrane in heterologous cells. Advances in this area have shed significant light on the fundamental factors governing the cell-specific control of olfactory receptor trafficking.     

Announcement

Announcement

Announcement     

Biological and Potential Therapeutic Roles of Sirtuin Deacetylases

Sirtuins comprise a unique class of nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylases that target multiple protein substrates to execute diverse biological functions. These enzymes are key regulators of clinically important cellular and organismal processes, including metabolism, cell division and aging. The desire to understand the important determinants of human health and lifespan has resulted in a firestorm of work on the seven mammalian sirtuins in less than a decade. The implication of sirtuins in medically important areas such as diabetes, cancer, cardiovascular dysfunction and neurodegenerative disease has further catapulted them to a prominent status as potential targets for nutritional and therapeutic development. Here, we present a review of published results on sirtuin biology and its relevance to human disease. Received 25 June 2008; received after revision 20 August 2008; accepted 29 August 2008     

Na+ binding to meizothrombin desF1

Meizothrombin is the physiologically active intermediate generated by a single cleavage of prothrombin at R320 to separate the A and B chains. Recent evidence has suggested that meizothrombin, like thrombin, is a Na(+)-activated enzyme. In this study we present the first X-ray crystal structure of human meizothrombin desF1 solved in the presence of the active site inhibitor PPACK at 2.1 A resolution. The structure reveals a Na(+) binding site whose architecture is practically identical to that of human thrombin. Stopped-flow measurements of Na(+) binding to meizothrombin desF1 document a slow phase of fluorescence change with a k(obs) decreasing hyperbolically with increasing [Na(+)], consistent with the existence of three conformations in equilibrium, E*, E and E:Na(+), as for human thrombin. Evidence that meizothrombin exists in multiple conformations provides valuable new information for studies of the mechanism of prothrombin activation.     

The three-fingered protein domain of the human genome

Extracellular domains of some cellular receptors expressed in the organisms at different levels of development belong to three-fingered protein (TFP) fold. The Homo sapiens genome encodes at least 45 genes containing from one to three TFP domains (TFPDs), namely diverse paralogues of the Ly6 gene, CD59 and the receptors of activins, bone morphogenetic proteins, Mullerian inhibiting substance and transforming growth factor-β. C4.4a and urokinase/plasminogen activatory receptor contain two and three TFPD repeats, respectively. These diverse proteins have a low overall sequence similarity with each other and their hydrophobicity levels vary to a considerable degree. It is suggested that sequence differentiation within the TFPD led to distinct groups of proteins whose attributes were optimized to fit both the physicochemical properties specific to their functional microenvironment and selective targeting of their highly diversified extracellular cofactors. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Received 7 August 2008; accepted 29 August 2008     

Strong association of de novo copy number mutations with sporadic schizophrenia

Schizophrenia is an etiologically heterogeneous psychiatric disease, which exists in familial and nonfamilial (sporadic) forms. Here, we examine the possibility that rare de novo copy number (CN) mutations with relatively high penetrance contribute to the genetic component of schizophrenia. We carried out a whole-genome scan and implemented a number of steps for finding and confirming CN mutations. Confirmed de novo mutations were significantly associated with schizophrenia (P = 0.00078) and were collectively approximately 8 times more frequent in sporadic (but not familial) cases with schizophrenia than in unaffected controls. In comparison, rare inherited CN mutations were only modestly enriched in sporadic cases. Our results suggest that rare de novo germline mutations contribute to schizophrenia vulnerability in sporadic cases and that rare genetic lesions at many different loci can account, at least in part, for the genetic heterogeneity of this disease.