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Biomedical subjects

S F Fan

Publications and source records attributed to S F Fan.

43 records · Page 3Linked to original sources
PubMedDate not supplied

Cannabinoid receptors on goldfish retinal bipolar cells: electron-microscope immunocytochemistry and whole-cell recordings.

Cannabinoid CB1 receptors are distributed throughout the CNS and interact with GABA, glutamate, and dopamine systems. Cannabinoids have effects on the visual system, some of which may have a retinal component, particularly the enhancement of photosensitivity. We used immunocytochemistry and whole-cell recording to study cannabinoids in the goldfish retina. Immunoblots of an antiserum against amino acids (1-14) of the rat CB1 receptor produced a single band in goldfish retina at about 70 kDa. Light microscope immunocytochemistry of CB1 receptor immunoreactivity (CB1R-IR) revealed intense staining of Müller cells and weaker staining of ON bipolar cells (verified with double labeling with PKC-IR) and the outer and inner plexiform layers. Ultrastructural analysis revealed that CB1R-IR was localized intracellularly as well as on the plasma membrane of photoreceptor terminals, bipolar cell terminals and, rarely, amacrine cell boutons. Membrane-associated CB1R-IR was restricted to cone pedicles at sites removed from the synaptic ribbon. Regarding bipolar cells, membrane-associated CB1R-IR was found at 93% of the synaptic terminals in sublamina b (ON-type) and only at 33% of the synaptic terminals in sublamina a (OFF-type). Whole-cell recordings from large ON-type Mb bipolar cells showed that the delayed rectifier (I(K(V))) was rapidly and reversibly inhibited by 1 microM of the cannabinoid agonists CP 54490 and (+)-WIN 55212-2, effects blocked completely by the antagonist SR 141716A (1 microM). Inhibition of I(K(V)) in the Mb bipolar cells by cannabinoids should result in a more tonic ON response to increments of light. As such, cannabinoids may play a role in modulating the temporal aspects of signaling in the retina.

Animals↗
PubMedDate not supplied

Dopamine depletion with 6-OHDA enhances dopamine D1-receptor modulation of potassium currents in retinal bipolar cells.

Ascorbate modulates IK(V) of ON-type mixed rod/cone bipolar cells (Mb) in the goldfish retinal slice through a dopamine D1/G-protein/PKA-coupled mechanism. We investigated the effects of dopamine depletion with intraocular injections of 6-OHDA on IK(V) and its modulation by ascorbate over 1-7 weeks following 6-OHDA treatment. Dopamine depletion was verified by tyrosine hydroxylase immunocytochemistry. Slices were perfused in a saline containing 200 microM sodium ascorbate. One-second puffs of ascorbate-free saline (zero [AA]o), delivered through a 2-3 microm diameter pipette, were directed at the bipolar cells. IK(V) was recorded by conventional whole-cell patch-clamp methods. In normal retinas, puffs of zero [AA]o caused a rapid (<100 ms) suppression of IK(V) of about 50% that lasted for several minutes. This effect was blocked by 1 microM SCH23390 and was unaffected by 2 mM Co2+ or 5 microM spiperone. 6-OHDA treatment resulted in major effects. First, IK(V) was reduced by approximately 50% for weeks 1-6, recovering to a 20% reduction by week 7. Second, puffs of zero [AA]o enhanced IK(V) rather than suppressed it. The enhancement was blocked by SCH23390 and the PKA inhibitor, Wiptide, but was insensitive to spiperone. Third, all parts of the Mb bipolar cell (except for the axon) were sensitive to puffs of zero [AA]o in both normal and 6-OHDA-treated retinas. Fourth, bath application of 20 microM dopamine restored the amplitude of IK(V) but did not reverse the effects of puffed zero [AA]o. IK(V) was fit by two exponentials; all of the effects on IK(V) were on the amplitude of the components and not on the time constants. Chronic dopamine depletion caused reversible changes in the properties of K+ channels underlying IK(V), as well as a long-term change in the intracellular coupling mechanisms between D1-receptor activation and the modulation of IK(V).

Adrenergic Agents↗
PubMedDate not supplied

Suppression of voltage-dependent K+ currents in retinal bipolar cells by ascorbate.

Ascorbate, often used as an antioxidant in neural studies, may also serve as a neuromodulator in the vertebrate central nervous system (CNS), in that it modulates the synaptic actions of glutamate and dopamine. Retina of fish contain a high concentration of ascorbate. The release and/or uptake of neurotransmitters are related to membrane potential, which to a large extent is determined by the activity of K+ channels. As retinal bipolar cells are subject to synaptic input from glutamatergic and dopaminergic sources, the effects of ascorbate on voltage-dependent K+ currents (I(K)(v)) of the mixed rod-cone ON-center bipolar cells (Mb) in goldfish retinal slices were studied using whole-cell recording techniques. I(K)(V) was suppressed reversibly 60% by 100-200 microM ascorbate. The effect of ascorbate was not due to changes in pH, oxidative stress, lipid peroxidation, any Ca2+-dependent or Na+-dependent action. However, the suppressive effect of ascorbate was blocked by cholera toxin and Wiptide, a protein kinase A (PKA) inhibitor. It is concluded that ascorbate, at physiological concentrations, inhibits I(K)(V) of bipolar cells via a Gs-protein-PKA system. This effect of ascorbate should be taken into account when using ascorbate as an antioxidant in retinal studies involving dopamine.

Animals↗
PubMedDate not supplied

Modulation of voltage-dependent K+ currents (IK(V)) in retinal bipolar cells by ascorbate is mediated by dopamine D1 receptors.

Ascorbic acid (AA), a neuromodulator in the vertebrate CNS, is released from glutamatergic neurons in exchange with glutamate uptake and, in turn, modulates the release of both glutamate and dopamine. We have reported that voltage-gated K+ currents (IK(V)) in ON-mixed rod/cone bipolar cells (Mb) were suppressed 60% by 100-200 microM AA when added to an ascorbate-free solution. However, as the in vivo [AA]o in retina is about 200 microM, we studied the effects of changes in [AA]o on IK(V) when [AA]o was varied around a baseline concentration of 200 microM. Whole-cell currents were recorded with patch-clamp methods from goldfish Mb cells in retinal slices, bathed in a solution containing 200 microM AA. We found that (1) IK(V) was enhanced (180+/-36%, n = 9) by increases of [AA]o less than 40 microM with an average latency of 8 min. (2) However, IK(V) was suppressed without an appreciable latent period by two conditions: increases more than 40 microM [AA]o and decreases by any amount greater than 10 microM. (3) Effects of delta[AA]o on IK(V) were blocked by a D1 dopamine receptor antagonist, SCH 23390, but not by a D2 receptor antagonist, spiperone. Increased concentrations of a D1 agonist (SKF 38390) and dopamine had similar concentration-dependent effects on IK(V) as did AA, even in the presence of 200 microM ascorbate. Ascorbate has complicated concentration-dependent effects on IK(V) of Mb cells in vitro that were mediated by D1 dopamine receptors, suggesting that dopamine and ascorbate may be involved reciprocally in modulating IK(V), with consequences on the transmission of rod signals to the inner retina.

Animals↗
PubMedDate not supplied

Weekly CAF chemotherapy for advanced breast cancer patients.

In a prospective phase II study, 102 women with advanced breast cancer were treated with low doses of cyclophosphamide, Adriamycin and 5-fluorouracil (CAF) at weekly intervals by intravenous injection. Seventy-five patients were evaluable for treatment response and the overall response rate was 52% (95% confidence interval, 41-63%). Of the evaluable patients, 15% had complete response and 37% had partial response. The median survival after therapy was 15.6 months, the median time to progression was 6.8 months and the median duration of response was 9.1 months. The main toxicities were mild vomiting and moderate myelosuppression. There was only 1 patient who experienced heart failure. Weekly CAF appears to have an efficacy with tolerable side effects comparable to standard CAF with an every-3-week schedule.

Adult↗