PubMed · 1691510
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M A Moscarello. 1990. Myelin basic protein: a dynamically changing structure.. https://pubmed.ncbi.nlm.nih.gov/1691510/
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Until recently, the therapeutic effects of furocoumarins and furochromones plus UV-A light were thought to be due to their ability to form photoadducts with DNA in the cell nuclei; now it appears that membrane effector systems may be involved as targets. Here we show that in HeLa cells khellin at 1 and 5 microM final concentration, in combination with UV-A light, inhibits NaF-stimulated adenylyl cyclase activity and Pertussis Toxin (PT)-catalyzed ADP-ribosylation of alpha-subunits of inhibitory guanine nucleotide regulatory proteins (Gi) and increases GTPase activity. In the same experimental conditions, 8-methoxypsoralen (8-MOP), either alone or plus UV-A, does not affect adenylyl cyclase and GTPase activities. Our results suggest that in HeLa cells, through an interaction with a receptor and the mediation of Gi proteins, the adenylyl cyclase system is a target for khellin but not for 8-MOP.
Poly(ADP-ribose) metabolism plays an important role in numerous DNA-related functions. This homopolymer is synthesized by poly(ADP-ribose) polymerase and is degraded mainly by the poly(ADP-ribose) glycohydrolase. The activities of these two enzymes in the nucleus are closely coordinated. To better understand the interactions between these enzymes, we designed an in vitro system in which both enzymes are present at the same time. In this work, we report a model describing the synthesis and degradation of the poly(ADP-ribose) in turnover conditions. Because the half-life of the polymer in the cell is close to 1 min, we studied the very early kinetic interactions of these two enzymes.
We have previously shown that agonist-induced Ca2+ mobilization in intestinal longitudinal muscle is mediated by ryanodine-sensitive, inositol 1,4,5-trisphosphate-insensitive sacroplasmic Ca2+ channels. Ca2+ release via these channels is triggered by agonist-stimulated Ca2+ influx and results in Ca(2+)-induced Ca2+ release. The present study examined whether cyclic ADP-ribose (cADPR) is synthesized in response to stimulation of longitudinal muscle by agonists and modulates the activity of Ca2+ release channels. Cyclic ADPR bound with high affinity to dispersed longitudinal muscle cells (IC50 1.9nM) and induced Ca2+ release (EC50 3.8 nM), increase in [Ca2+]i (EC50 2.0 nM), and contraction (EC50 1.1 nM); cADPR had no effect on circular muscle cells. The effects of cADPR were blocked by ruthenium red, dantrolene, and the specific antagonist, 8-amino-cADPR, and were augmented by caffeine but not affected by heparin. The binding of cADPR and its ability to stimulate Ca2+ release were dependent on the concentration of Ca2+. Cyclic ADPR was capable of stimulating Ca2+ release at subthreshold Ca2+ concentrations (25-100 nM) and of enhancing Ca(2+)-induced Ca2+ release. Longitudinal muscle extracts incubated with beta-NAD+ produced a time-dependent increase in Ca(2+)-mobilizing activity identified as authentic cADPR by blockade of Ca2+ release with 8-amino-cADPR and ruthenium red. Ca2+ mobilizing activity was increased by cholecystokinin octapeptide (CCK-8) in a concentration-dependent fashion. The increase induced by CCK-8 was suppressed by the CCK-A antagonist, L364,718, nifedipine, and guanyl-5'-yl thiophosphate. The study shows that ADP-ribosyl cyclase can be stimulated by agonists and that cADPR can act as an endogenous modulator of Ca(2+)-induced Ca2+ release.