In cultured rat dorsal root ganglia neurons, we measured membrane currents, using the patch±clamp whole-cell technique, and the concentrations of free Ca 2+ in the cytosol (

It is well documented that the hormone leptin plays a pivotal role in regulating food intake and body weight via its hypothalamic actions. However, leptin receptors are expressed throughout the brain with high levels found in the hippocampus. Evidence is accumulating that leptin has widespread actions on CNS function and in particular learning and memory. Recent studies have demonstrated that leptin-deficient or-insensitive rodents have impairments in hippocampal synaptic plasticity and in spatial memory tasks performed in the Morris water maze. Moreover, direct administration of leptin into the brain facilitates hippocampal long-term potentiation (LTP), and improves memory performance in mice. There is also evidence that, at the cellular level, leptin has the capacity to convert hippocampal short-term potentiation (STP) into LTP, via enhancing NMDA receptor function. Recent data indicates that leptin can also induce a novel form of NMDA receptor-dependent hippocampal long-term depression. Here, we review the evidence implicating a key role for the hormone leptin in modulating hippocampal synaptic plasticity and discuss the role of lipid signaling cascades in this process.

Interleukin-1 is a primary mediator of immune responses to injury and infection, but the mechanism of its cellular release is unknown. IL-1 exists as two agonist forms (IL-1α and IL-1β) present in the cytosol of activated monocytes/macrophages. IL-1β is synthesized as an inactive precursor that lacks a signal sequence, and its trafficking does not use the classical endoplasmic reticulum-Golgi route of secretion. Using primary cultured murine peritoneal macrophages, we demonstrate that P2X7 receptor activation causes release of IL-1β and IL-1α via a common pathway, dependent upon the release of Ca2+ from endoplasmic reticulum stores and caspase-1 activity. Increases in intracellular Ca2+ alone do not promote IL-1 secretion because a concomitant efflux of K+ through the plasmalemma is required. In addition, we demonstrate the existence of an alternative pathway for the secretion of IL-1α, independent of P2X7 receptor activation, but dependent upon Ca2+ influx. The identification of these mechanisms provides insight into the mechanism of IL-1 secretion, and may lead to the identification of targets for the therapeutic modulation of IL-1 action in inflammation.

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