Mode of action of ICS 205,930, a novel type of potentiator of responses to glycine in rat spinal neurones

1. The effect of a novel potentiator of glycine responses, ICS 205,930, was studied by whole-cell recordings from spinal neurones, and compared with that of other known potentiators, in an attempt to differentiate their sites of action. 2. The ability of ICS 205,930 (0.2 μM) to potentiate glycine responses persisted in the presence of concentrations of Zn(2+) (5–10 μM) that were saturating for the potentiating effect of this ion. 3. Preincubation with 10 μM Zn(2+) before application of glycine plus Zn(2+) had an inhibitory effect, which did not result from Zn(2+) entry into the neurone, since it persisted with either 10 mM internal EGTA or 10 μM internal Zn(2+). To test whether the potentiating effects of ICS 205,930 and Zn(2+) interact, both compounds were applied without preincubation. 4. The potentiating effect of ICS 205,930 was similar for responses to glycine and for responses to glycine plus Zn(2+), provided the concentrations of agonist were adjusted so as to induce control responses of identical amplitudes. 5. ICS 205,930 remained able to potentiate glycine responses in the presence of ethanol (200 mM). 6. ICS 205,930 also retained its potentiating effect in the presence of the anaesthetic propofol (30–90 μM), which strongly potentiated glycine responses but, in contrast with ICS 205,930, also markedly increased the resting conductance. 7. The anticonvulsant chlormethiazole (50–100 μM) neither potentiated glycine responses nor prevented the effect of ICS 205,930, even though it increased the resting conductance and potentiated GABA(A) responses. 8. The mechanism of action of ICS 205,930 appears to be different from those by which Zn(2+), propofol or ethanol potentiate glycine responses

Induction of a low voltage-activated, fast-inactivating Ca2+ channel in cultured bone marrow stromal cells by dexamethasone

The production of biochemical markers associated with the osteoblastic phenotype, and accompanying changes in the expression of voltage-operated Ca2+ channels, have been examined in rat bone marrow stromal cell cultures treated with dexamethasone (10(-8) M). Whole cell clamp analysis of voltage-operated Ca2+ channels in control cultures (using Ba2+ as the charge carrier) revealed primarily a high voltage-activated (HVA), slowly inactivating current, which was enhanced two- to threefold by treatment of the cells with Bay K 8644 (300 nM) and inhibited by nifedipine (4 mu M). In dexamethasone-treated cultures, the I-V relationship for inward current was shifted to more positive potentials in comparison with control cells. Most cells in these cultures possessed both the HVA current and also a faster inactivating, low-voltage-activated (LVA), nifedepine-resistant current. These two currents could be separated both by nifedipine and by the use of steady state inactivation of the LVA current. The two components of the Ba2+ current varied widely in their relative size. The combination of LVA and HVA currents seen in dex-induced stromal cells resembles records of voltage-operated Ca2+ channels from cultures of calvarial osteoblasts