Biomedical subjects

Andrew Charles

Publications and source records attributed to Andrew Charles.

5 recordsLinked to original sources

PubMed2005

Teaching resources. Glial intercellular waves.

Glial cells have long been assigned a supporting role in the nervous system, in which they help maintain and modulate neuronal metabolism. However, recent attention has focused on the ability of astrocytes to propagate long-range calcium signals and actively communicate with each other, as well as with neurons and vascular cells. Synaptic activity in neurons triggers an increase in the intracellular calcium concentration ([Ca2+]i) of neighboring astrocytes, stimulating the release of ATP and glutamate. The released ATP stimulates an increase in [Ca2+]i in neighboring astrocytes so that a "calcium wave" is propagated from cell to cell. Released glutamate is cotransported with Na+ into neighboring cells; thus, glutamate uptake leads to an increase in astrocyte intracellular sodium concentration ([Na+]i) that is also propagated from cell to cell. This increase in [Na+]i stimulates an increase in glucose uptake and metabolism that leads to the formation of lactate, which is delivered to nearby--and perhaps distant--neurons as an energy substrate. Thus, long-range intercellular calcium signaling in astrocytes may enable them to spatially coordinate their function in supporting neuronal metabolism.

Adenosine Triphosphate↗

PubMed2005

Reaching out beyond the synapse: glial intercellular waves coordinate metabolism.

Neuronal activity can stimulate an increase in astrocyte intracellular calcium concentration, which is propagated through neighboring astrocytes as a "calcium wave"; these calcium waves are accompanied by the release of glutamate. Sodium-dependent glutamate uptake leads to a secondary astrocytic sodium wave, accompanied by a wave of increased glucose uptake and metabolism. This metabolic wave may enable astrocytes to provide lactate as an energy source to neighboring active neurons and perhaps to distant neurons as well. Thus, one function of long-range intercellular calcium signaling in astrocytes may be to spatially coordinate their function in supporting neuronal metabolism.

Adenosine Triphosphate↗

PubMed2004

Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer.

PURPOSE: The human epidermal growth factor receptor (EGFR) plays an oncogenic role in solid cancer, including brain cancer. The present study was designed to prolong survival in mice with intracranial human brain cancer with the weekly i.v. injection of nonviral gene therapy causing RNA interference (RNAi) of EGFR gene expression. EXPERIMENTAL DESIGN: Human U87 gliomas were implanted in the brain of adult scid mice, and weekly i.v. gene therapy was started at day 5 after implantation of 500000 cells. An expression plasmid encoding a short hairpin RNA directed at nucleotides 2529-2557 within the human EGFR mRNA was encapsulated in pegylated immunoliposomes. The pegylated immunoliposome was targeted to brain cancer with 2 receptor-specific monoclonal antibodies (MAb), the murine 83-14 MAb to the human insulin receptor and the rat 8D3 MAb to the mouse transferrin receptor. RESULTS: In cultured glioma cells, the delivery of the RNAi expression plasmid resulted in a 95% suppression of EGFR function, based on measurement of thymidine incorporation or intracellular calcium signaling. Weekly i.v. RNAi gene therapy caused reduced tumor expression of immunoreactive EGFR and an 88% increase in survival time of mice with advanced intracranial brain cancer. CONCLUSIONS: Weekly i.v. nonviral RNAi gene therapy directed against the human EGFR is a new therapeutic approach to silencing oncogenic genes in solid cancers. This is enabled with a nonviral gene transfer technology that delivers liposome-encapsulated plasmid DNA across cellular barriers with receptor-specific targeting ligands.

Animals↗

PubMed2003

Riluzole inhibits spontaneous Ca2+ signaling in neuroendocrine cells by activation of K+ channels and inhibition of Na+ channels.

The neuroprotective drug riluzole has multiple effects on cellular signaling. We found that riluzole rapidly and reversibly inhibited spontaneous Ca2+ oscillations in both immortalized GnRH-secreting hypothalamic neurons (GT1 cells) and in the prolactin and growth-hormone-secreting GH3 cell line. At lower concentrations (100 nm-5 microM), riluzole reduced the amplitude and frequency of spontaneous Ca2+ oscillations, whereas at higher concentrations it abolished spontaneous Ca2+ signaling. Whole-cell current clamp recordings in GH3 cells revealed that riluzole decreased the action potential frequency, amplitude, and duration. Riluzole inhibited voltage-gated Na+ currents, increased iberiotoxin-sensitive voltage-gated K+ currents, and had no effect on voltage-gated Ca2+ currents in GH3 cells. Riluzole also inhibited voltage-gated Na+ currents and increased voltage-gated K+ channels in GT1 cells. The inhibitory effects of riluzole on Ca2+ signaling were blocked by pretreatment with iberiotoxin in GH3 cells, but only partially reduced by iberiotoxin in GT1 cells. These results indicate that riluzole inhibits Ca2+ signaling primarily by activation of K+ channels in GH3 cells, and also by inhibition of Na+ channels in GT1 cells. Riluzole's inhibition of spontaneous excitability and Ca2+ signaling may be involved in its multiple effects on cellular function in the nervous system.

Action Potentials↗

PubMed2003

Modulation of intercellular calcium signaling in astrocytes by extracellular calcium and magnesium.

The extracellular concentrations of Ca(2+) and Mg(2+) are well known to play important roles in the function of the central nervous system. We examined the effects of extracellular Ca(2+) and Mg(2+) on ATP release and intercellular signaling in astrocytes. The extent of propagation of intercellular Ca(2+) waves evoked by mechanical stimulation was increased by reduction of extracellular Ca(2+) ([Ca(2+)](o)) or Mg(2+) concentration ([Mg(2+)](o)) and was decreased by elevated [Mg(2+)](o). Reduction of extracellular Ca(2+) concentration ([Ca(2+)](o)) evokes intercellular Ca(2+) signaling in astrocytes; a similar effect was observed in response to change from 5 mM [Mg(2+)](o) to 0 [Mg(2+)](o). Release of low-molecular-weight dyes and ATP was also activated by low [Ca(2+)](o) or [Mg(2+)](o) and inhibited by high [Ca(2+)](o) or [Mg(2+)](o). Astrocytes showed low [Ca(2+)](o)-activated whole cell currents consistent with currents through connexin hemichannels. These currents were inhibited by extracellular Mg(2+). We conclude that extracellular divalent cations modulate intercellular Ca(2+) signaling in astrocytes by modulating the release of ATP, possibly via connexin hemichannels.

Adenosine Triphosphate↗