University of Dundee

About: University of Dundee is a education organization based out in Dundee, United Kingdom. It is known for research contribution in the topics: Population & Protein kinase A. The organization has 19258 authors who have published 39640 publications receiving 1919433 citations. The organization is also known as: Universitas Dundensis & Dundee University.

A Reevaluation of the Role of Mitochondria in Neuronal Ca2+ Homeostasis

Abstract: The ability of mitochondrial Ca 2+ transport to limit the elevation in free cytoplasmic Ca 2+ concentration in neurones following an imposed Ca 2+ load is reexamined. Cultured cerebellar granule cells were monitored by digital fura-2 imaging. Following KCl depolarization, addition of the protonophore carbonylcyanide m-chlorophenylhydrazone (CCCP) to depolarize mitochondria released a pool of Ca 2+ into the cytoplasm in both somata and neurites. No CCCP-releasable pool was found in nondepolarized cells. Although the KCl-evoked somatic and neurite Ca 2+ concentration elevations were enhanced when CCCP was present during KCl depolarization, this was associated with a collapsed ATP/ADP ratio. In the presence of the ATP synthase inhibitor oligomycin, glycolysis maintained high ATP/ADP ratios for at least 10 min. The further addition of the mitochondrial complex I inhibitor rotenone led to a collapse of the mitochondrial membrane potential, monitored by rhodamine-123, but had no effect on ATP/ADP ratios. In the presence of rotenone/oligomycin, no CCCP-releasable pool was found subsequent to KCl depolarization, consistent with the abolition of mitochondrial Ca 2+ transport ; however, paradoxically the KCl-evoked Ca 2+ elevation is decreased. It is concluded that the CCCP-induced increase in cytoplasmic Ca 2+ response to KCl is due to inhibition of nonmitochondrial ATP-dependent transport and that mitochondrial Ca 2+ transport enhances entry of Ca 2+ , perhaps by removing the cation from cytoplasmic sites responsible for feedback inhibition of voltage-activated Ca 2+ channel activity.

TRANSPORT OF INDOLEACETIC ACID IN PLANT CELLS IN RELATION TO pH AND ELECTRICAL POTENTIAL GRADIENTS, AND ITS SIGNIFICANCE FOR POLAR IAA TRANSPORT

Abstract: SUMMARY The distribution of IAA between the vacuole and the bathing solution in Hydrodictyon africanum is consistent with passive entry of undissociated IAA and passive efflux of both undissociated IAA and of IAA-, with PIAA (permeability coefficient)* about io-3 cms-1 and PIAA- about -6 -1A o-6 cm s . The involvement of IAA- in the efflux results from the inside-negative P.D. between the medium and the vacuole. The cytoplasm is at a higher pH than either the vacuole or the bathing solution used in most experiments; this is maintained by active H+ efflux at the plasmalemma, and active influx at the tonoplast. In this situation the efflux of IAA- is further promoted by the increased concentration of IAA- in the relatively alkaline cytoplasm. Thus the apparent active efflux of IAA from these cells can be explained in terms of passive driving forces of concentration and electrical potential acting on IAA and IAA-, with the distribution of these two species dictated ultimately by PIAA, PIAA-) the pH of the various compartments and the electrical potential difference between them. If PIAA/PIAA- were larger at the apical than at the basal end of coleoptile cells, such an effect could explain polar IAA transport, with metabolic energy being used only to maintain the relative permeabilities to the two species, the pH gradient and the electrical gradient.

Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser910/Ser935, disruption of 14-3-3 binding and altered cytoplasmic localization

Abstract: LRRK2 (leucine-rich repeat protein kinase 2) is mutated in a significant number of Parkinson's disease patients. Since a common mutation that replaces Gly2019 with a serine residue enhances kinase catalytic activity, small-molecule LRRK2 inhibitors might have utility in treating Parkinson's disease. However, the effectiveness of inhibitors is difficult to assess, as no physiological substrates or downstream effectors have been identified that could be exploited to develop a robust cell-based assay. We recently established that LRRK2 bound 14-3-3 protein isoforms via its phosphorylation of Ser910 and Ser935. In the present study we show that treatment of Swiss 3T3 cells or lymphoblastoid cells derived from control or a Parkinson's disease patient harbouring a homozygous LRRK2(G2019S) mutation with two structurally unrelated inhibitors of LRRK2 (H-1152 or sunitinib) induced dephosphorylation of endogenous LRRK2 at Ser910 and Ser935, thereby disrupting 14-3-3 interaction. Our results suggest that H-1152 and sunitinib induce dephosphorylation of Ser910 and Ser935 by inhibiting LRRK2 kinase activity, as these compounds failed to induce significant dephosphorylation of a drug-resistant LRRK2(A2016T) mutant. Moreover, consistent with the finding that non-14-3-3-binding mutants of LRRK2 accumulated within discrete cytoplasmic pools resembling inclusion bodies, we observed that H-1152 causes LRRK2 to accumulate within inclusion bodies. These findings indicate that dephosphorylation of Ser910/Ser935, disruption of 14-3-3 binding and/or monitoring LRRK2 cytoplasmic localization can be used as an assay to assess the relative activity of LRRK2 inhibitors in vivo. These results will aid the elaboration and evaluation of LRRK2 inhibitors. They will also stimulate further research to understand how phosphorylation of Ser910 and Ser935 is controlled by LRRK2, and establish any relationship to development of Parkinson's disease.

The cancer chemopreventive actions of phytochemicals derived from glucosinolates

Abstract: This article reviews the mechanisms by which glucosinolate breakdown products are thought to inhibit carcinogenesis. It describes how isothiocyanates, thiocyanates, nitriles, cyano-epithioalkanes and indoles are produced from glucosinolates through the actions of myrosinase, epithiospecifier protein and epithiospecifier modifier protein released from cruciferous vegetables during injury to the plant. The various biological activities displayed by these phytochemicals are described. In particular, their abilities to induce cytoprotective genes, mediated by the Nrf2 (NF-E2 related factor 2) and AhR (arylhydrocarbon receptor) transcription factors, and their abilities to repress NF-κB (nuclear factor-κB) activity, inhibit histone deacetylase, and inhibit cytochrome P450 are outlined. Isothiocyanates appear to alter gene expression through modification of critical thiols in regulatory proteins such as Keap1 (Kelch-like ECH-associated protein 1) or IKK (IκB kinase), causing activation of Nrf2 and inactivation of NF-κB, respectively. Certain indoles act as ligands for AhR. Isothiocyanates and indoles are also capable of affecting cell cycle arrest and stimulating apoptosis. The mechanisms responsible for these anti-proliferative responses are discussed.

Reading habits for both words and numbers contribute to the SNARC effect

Abstract: This study compared the spatial representation of numbers in three groups of adults: Canadians, who read both English words and Arabic numbers from left to right; Palestinians, who read Arabic words and Arabic-Indic numbers from right to left; and Israelis, who read Hebrew words from right to left but Arabic numbers from left to right. Canadians associated small numbers with left and large numbers with right space (the SNARC effect), Palestinians showed the reverse association, and Israelis had no reliable spatial association for numbers. These results suggest that reading habits for both words and numbers contribute to the spatial representation of numbers.