Background: Thiol isomerases are a family of endoplasmic reticulum enzymes which orchestrate redox-based modifications of protein disulphide bonds. Previous studies have identified important roles for the thiol isomerases PDI and ERp5 in the regulation of normal platelet function. Aim: Recently, we demonstrated the presence of a further five thiol isomerases at the platelet surface. In this report we aim to report the role of one of these enzymes – ERp57 in the regulation of platelet function. Methods/Results: Using enzyme activity function blocking antibodies, we demonstrate a role for ERp57 in platelet aggregation, dense granule secretion, fibrinogen binding, calcium mobilisation and thrombus formation under arterial conditions. In addition to the effects of ERp57 on isolated platelets, we observe the presence of ERp57 in the developing thrombus in vivo. Furthermore the inhibition of ERp57 function was found to reduce laser-injury induced arterial thrombus formation in a murine model of thrombosis. Conclusions: These data suggest that ERp57 is important for normal platelet function and opens up the possibility that the regulation of platelet function by a range of cell surface thiol isomerases may represent a broad paradigm for the regulation of haemostasis and thrombosis.
Snakebite envenoming (SBE) is a priority neglected tropical disease, which kills in excess of 100,000 people per year. Additionally, many millions of survivors also suffer through disabilities and long-term health consequences. The only treatment for SBE, antivenom, has a number of major associated problems, not least, adverse reactions and limited availability. This emphasises the necessity for urgent improvements to the management of this disease. Administration of antivenom is too frequently based on symptomatology, which results in wasting crucial time. The majority of SBE-affected regions rely on broad-spectrum polyvalent antivenoms that have a low content of case-specific efficacious immunoglobulins. Research into small molecular therapeutics such as varespladib/methyl-varespladib (PLA2 inhibitors) and batimastat/marimastat (metalloprotease inhibitors) suggest that such adjunctive treatments could be hugely beneficial to victims. Progress into toxin-specific monoclonal antibodies as well as alternative binding scaffolds such as aptamers hold much promise for future treatment strategies. SBE is not implicit during snakebite, due to venom metering. Thus, the delay between bite and symptom presentation is critical and when symptoms appear it may often already be too late to effectively treat SBE. The development of reliable diagnostical tools could therefore initiate a paradigm shift in the treatment of SBE. While the complete eradication of SBE is an impossibility, mitigation is in the pipeline, with new treatments and diagnostics rapidly emerging. Here we critically review the urgent necessity for the development of diagnostic tools and improved therapeutics to mitigate the deaths and disabilities caused by SBE.
In 1967, a new era in endocrinology was born. A set of pulse chase experiments performed by Steiner and Oyer (1) elegantly showed, for the first time, that insulin was derived from a larger precursor molecule, proinsulin. The radical revelation, that bioactive peptides are derived from larger precursors, forever changed endocrinology and, from then on, the concept of hormone precursors (or prohormones) has become a central dogma. Subsequently, the use of both traditional protein sequence studies and recombinant DNA technology have provided definitive structures for the precursors of all the known bioactive peptides as well as identifying several previously unknown precursors, the function of which are still not fully understood. In general, all these molecules contain within their sequence one or more copies of the active peptide while some contain several different bioactive peptides. In addition, they undergo a series of highly regulated post-translational events that includes specific proteolytic cleavage and modifications such as amidation, acetylation and phophorylation. These post-translational processing events are especially interesting because there are a number of examples where the extent of processing can yield very different bioactive peptides from the same precursor. Probably the best example of this phenomenon, and arguably the most studied prohormone, is the ACTH precursor pro-opiomelanocortin (POMC). This short review aims to highlight why it has been of such interest to (neuro)endocrinologists and suggests that it still has a few more secrets to yield. Discovery of POMCThe discovery of POMC ( Fig. 1) was preceded by a number of what, at the time, appeared to be unrelated observations. Both ACTH and a-melanocyte-stimulating hormone (a-MSH) had been purified and sequenced from the pituitaries of various species. However, the fact that a-MSH has the same amino acid sequence as the first 13 residues of ACTH was not seen to be of much significance until the isolation of corticotrophin-like intermediate peptide (CLIP) (2), the peptide that comprises the C-terminal of ACTH. This, together with the identification of larger molecular weight forms of immunoreactive ACTH (3, 4), began to suggest that ACTH and a-MSH were indeed derived from the same molecule.A further observation suggesting the existence of a common precursor to a number of pituitary hormones was that the sequence of the newly-discovered pituitary peptide, b-endorphin (5, 6), which had strong opiate-like activity, shared the same sequence as the C-terminal of b-lipotrophin (b-LPH), another pituitary hormone released under the same conditions as ACTH. It was subsequently shown that b-LPH was expressed in the same pituitary cells as a-MSH and CLIP (7).In 1976, the first published report came that suggested ACTH and b-LPH were derived from the same molecule (8) It is just over 30 years since the definitive identification of the adrenocorticotrophin (ACTH) precursor, pro-opiomelanocotin (POMC). Although first characterised in the anterior and...
The adrenal gland requires stimuli from peptides derived from the ACTH precursor, pro-opiomelanocortin (POMC), to maintain its tonic state. Studies have proposed that a specific postsecretional cleavage of the nonmitogenic N-terminal 16 kDa fragment, also known as pro-gamma-melanotropin (pro-gamma-MSH), is required, releasing shorter fragments that promote adrenal growth. Here, we provide evidence for this hypothesis by the cloning and characterization of a serine protease that is upregulated during growth of the adrenal cortex. It is expressed exclusively in the outer adrenal cortex, the site of cell proliferation, and in the Y1 adrenal cell line. We also show that it is required for growth of Y1 cells, remains bound to the cell surface, and cleaves its substrate, pro-gamma-MSH, at a specific bond.
Insulin-like peptide 3 (INSL3), a major product of testicular Leydig cells, is also expressed by the ovary, but its functional role remains poorly understood. Here, we quantified expression of INSL3 and its receptor RXFP2 in theca interna cell (TIC) and granulosa cell compartments of developing bovine antral follicles and in corpora lutea (CL). INSL3 and RXFP2 mRNA levels were much higher in TIC than granulosa cell and increased progressively during follicle maturation with INSL3 peaking in large (11-18 mm) estrogen-active follicles and RXFP2 peaking in 9- to 10-mm follicles before declining in larger (11-18 mm) follicles. Expression of both INSL3 and RXFP2 in CL was much lower than in TIC. In situ hybridization and immunohistochemistry confirmed abundant expression of INSL3 mRNA and protein in TIC. These observations indicate follicular TIC rather than CL as the primary site of both INSL3 production and action, implying a predominantly autocrine/paracrine role in TIC. To corroborate the above findings, we showed that in vitro exposure of TIC to a luteinizing concentration of LH greatly attenuated expression of both INSL3 and its receptor while increasing progesterone secretion and expression of STAR and CYP11A1. Moreover, in vivo, a significant cyclic variation in plasma INSL3 was observed during synchronized estrous cycles. INSL3 and estradiol-17β followed a similar pattern, both increasing after luteolysis, before falling sharply after the LH surge. Thus, theca-derived INSL3, likely from the dominant preovulatory follicle, is detectable in peripheral blood of cattle, and expression is down-regulated during luteinization induced by the preovulatory LH surge. Collectively, these findings underscore the likely role of INSL3 as an important intrafollicular modulator of TIC function/steroidogenesis, while raising doubts about its potential contribution to CL function.
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