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Physiological and pathophysiological aspects of ceramide.

Activation of cells by receptor- and nonreceptor-mediated stimuli not only requires a change in the activity of signaling proteins but also requires a reorganization of the topology of the signalosom in the cell. The cell membrane contains distinct domains, rafts that serve the spatial organization of signaling molecules in the cell. Many receptors or stress stimuli transform rafts by the generation of ceramide. These stimuli activate the acid sphingomyelinase and induce a translocation of this enzyme onto the extracellular leaflet of the cell membrane. Surface acid sphingomyelinase generates ceramide that serves to fuse small rafts and to form large ceramide-enriched membrane platforms. These platforms cluster receptor molecules, recruit intracellular signaling molecules to aggregated receptors, and seem to exclude inhibitory signaling factors. Thus ceramide-enriched membrane platforms do not seem to be part of a specific signaling pathway but may facilitate and amplify the specific signaling elicited by the cognate stimulus. This general function may enable these membrane domains to be critically involved in the induction of apoptosis by death receptors and stress stimuli, bacterial and viral infections of mammalian cells, and the regulation of cardiovascular functions.

Animals↗

Inhibition of mechanosensory interneurons in the crayfish. I. Presynaptic inhibition from giant fibers.

1. Sucrose-gap and intracellular recordings were used to study the primary afferent depolarization (PAD) produced in mechanosensory afferents by impulses in lateral and medial giant axons, which are the command cells for the tail flip escape response in the crayfish. 2. The lateral and medial giant axons produce PAD through a polysynaptic interneuronal pathway. The response has a relatively long intraganglionic latency (7--11 ms), and command-evoked PAD can be recorded in ganglia from which the giant axons have been experimentally disconnected. 3. The final neurons of the pathway that delivers inhibition are few in number and extensive in distribution; most appear to be common to lateral and medial giant pathways. 4. At least some of the inhibitory interneurons have axons in the interganglionic connectives and probably produce both presynaptic and postsynaptic inhibition. 5. Stimulation of the lateral, but not the medial, giant axons causes a small, short-latency deplorization that is stable at high repetition rates. This small potential can be accounted for by transmission across known electrical synapses between mechanosensory afferents and the lateral giants in each abdominal ganglion. 6. Repetitive stimulation of the lateral giant axons causes substantial augmentation of PAD, apparently through recruitment of additional interneurons. PAD evoked by a single medial giant (MG) stimulus is generally much larger than that elicited by a single lateral giant (LG) spike. However, MG-PAD summates little and so the maximum PAD deltaV reached during repetitive firing is equivalent for the two types of giant axons. 7. Iontophoresis of gamma-aminobutyric acid (GABA) into the ganglionic neuropil depolarizes the primary afferents and blocks activity in neurons that have axons in the interganglionic connective. 8. The extrapolated PAD reversal potential and pharmacological studies suggest that a GABA-mediated chloride conductance increase is involved in the production of PAD.

Animals↗

A biobehavioral model of obesity.

Recent research contributing to an increased understanding of human feeding is reviewed and implications for obesity discussed. Hyperphagia may represent the manifestation of diverse origins requiring different therapeutic strategies. A biobehavioral model of obesity designed to promote increased efficacy of treatment interventions with the overweight is proposed.

Animals↗