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Neuropharmacology and Cell Signalling

Elucidation of the molecular mechanisms by which general anesthetics act is an important goal in neuropharmacology. This is necessary for the development of safer and more specific anesthetic agents. Electrophysiological evidence indicates that general anesthetics act primarily on synaptic transmission without major effects on axonal conduction or neuronal excitability. At clinically relevant concentrations, most general anesthetics depress excitatory synaptic transmission, while some, including propofol and barbiturates, facilitate inhibitory synaptic transmission. There is good evidence for both presynaptic and postsynaptic mechanisms for these effects, including presynaptic reductions in excitatory neurotransmitter release, inhibition of postsynaptic responses to excitatory neurotransmitters, and facilitation of postsynaptic responses to inhibitory neurotransmitters. However, the precise molecular mechanisms involved in these effects are unknown. In my laboratory. The effects of various general anesthetics on neurotransmitter release (e.g., glutamate, GABA, norepinephrine, dopamine, neuropeptides) and on the interactions between specific presynaptic proteins involved in the control of neurotransmitter release (e.g., SNAREs) are being studied in isolated nerve terminals and using purified recombinant proteins. The effects of general anesthetics on presynaptic ion channels are being characterized in isolated neurohypophysial nerve terminals by patch clamp electrophysiological analysis. The role of protein kinase (PKC) as a target of general anesthetic actions is being studied using biochemical and imaging techniques. The basic biochemical mechanisms involved in the regulation of protein phosphatase activity in neurons are also being investigated. Previous studies have identified an endogenous neuronal protein phosphatase inhibitor that is an important molecular integrator of multiple converging cellular signals in dopaminoceptive neurons. We are currently identifying and characterizing specific targeting subunits for protein phosphatase-1 in neurons. Current studies focus on the regulation and interactions of one such protein, neurabin. For further information: Pharmacology Home Page