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R J Webster

Publications and source records attributed to R J Webster.

3 recordsLinked to original sources
PubMed1994

Sphingosine effects on the contractile behavior of skinned cardiac myocytes.

Sphingosine modulates myocyte beating behavior by acting on the sarcoplasmic reticulum calcium release channel, the ryanodine receptor. Chemically skinned myocytes isolated from adult rabbit ventricles exhibited spontaneous asynchonous contractions in response to micromolar levels of calcium. These cells do not have a functional sarcolemma but exhibit spontaneous contraction-relaxation cycles which are controlled by the sarcoplasmic reticulum. The intracellular second messenger, sphingosine, significantly reduced myocyte beat frequency in a biphasic manner with an IC50 of c. 0.5 microM. A computerized video-enhancement micrography system was used to determine the effect of sphingosine on sarcomere contractile parameters and to determine the potential source of the altered beating behavior produced by sphingosine. Contraction parameters related to sarcomere shortening were unaffected by sphingosine in the submicromolar range, suggesting that sphingosine had no effect on the contractile machinery itself. However, submicromolar sphingosine had a significant inhibitory effect on the spread of activation from sarcomere to sarcomere in these cells. Activation waves were propagated with an average velocity of 331 and 199 microns/s in control and sphingosine (0.58 microM) treated cells, respectively. Permeabilized myocyte calcium uptake was markedly increased by treatment with sphingosine, consistent with an inhibitory effect of sphingosine on sarcoplasmic reticulum calcium release. Sphingosine blocked calcium-induced calcium release from isolated cardiac sarcoplasmic reticulum membranes containing the ryanodine receptor. The results suggest that the site of sphingosine action on calcium signaling and beating behavior in the cardiac cell is the sarcoplasmic reticulum ryanodine receptor. By inhibiting channel opening sphingosine may increase the calcium threshold necessary to trigger calcium-induced calcium release, thus modulating cardiac excitation-contraction coupling.

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PubMed1989

Relationship between inducible H-2 expression and the immunogenicity of murine skin neoplasms. I. Evidence that the immunogenicity of ultraviolet radiation-chemically induced tumors is associated with their susceptibility to gamma-interferon-mediated enhancement of H-2Kk expression.

Our objective was to determine the relationship between major histocompatibility complex class I molecule expression and the tumorigenic properties of cutaneous neoplasms induced by ultraviolet radiation or chemical carcinogens. All tumors tested were found to express low constitutive levels of MHC class I molecules in vitro as determined by indirect immunofluorescence and flow cytometry. Those tumors capable of growth in UVR-exposed but not in normal recipients (regressors) were found to express enhanced levels of H-2Kk following incubation in the presence of gamma-IFN. In contrast, only one of the tumors that were capable of growth in normal recipients (progressors) exhibited more than moderate enhancement of H-2Kk expression in response to gamma-IFN. Analysis of tumor variants obtained by conversion of a UVR-induced regressor tumor to the progressor phenotype by passage through sublethally gamma-irradiated hosts, or the generation of regressor tumors by mutagen exposure of a benz [A] pyrene (BAP) induced progressor tumor, further supported the direct relationship between tumor immunogenicity in vivo and the capacity to elevate H-2Kk expression in response to gamma-IFN. No correlation existed between H-2Dk expression by the tumors and their transplantation phenotype. Furthermore, we failed to observe MHC class II expression by any of the tumors tested. Finally, the growth rate of a regressor tumor implanted into UVR-exposed hosts was significantly reduced if the tumor was pretreated with gamma-IFN in vitro prior to inoculation. This result suggests that UVR-exposed animals may be deficient in their ability to enhance the expression of MHC class I molecules on developing tumors. This alteration may, in part, account for the state of tumor susceptibility caused by UVR exposure.

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