Abstract-We reported upregulation of endothelial nitric oxide synthase (eNOS) by PGE 2 in tissues and presence of perinuclear PGE 2 receptors (EP). We presently studied mechanisms by which PGE 2 induces eNOS expression in cerebral microvessel endothelial cells (ECs). 16,16-Dimethyl PGE 2 and selective EP 3 receptor agonist M&B28767 increased eNOS expression in ECs and the NO-dependent vasorelaxant responses induced by substance P on cerebral microvessels. These effects could be prevented by prostaglandin transporter blocker bromcresol green and actinomycin D. EP 3 immunoreactivity was confirmed on plasma and perinuclear membrane of ECs. M&B28767 increased eNOS RNA expression in EC nuclei, and this effect was augmented by overexpression of EP 3 receptors. M&B28767 also induced increased phosphorylation of Erk-1/2 and Akt, as well as changes in membrane potential revealed by the potentiometric fluorescent dye RH421, which were prevented by iberiotoxin; perinuclear K Ca channels were detected, and their functionality corroborated by NS1619-induced Ca 2ϩ signals and nuclear membrane potential changes. Moreover, pertussis toxin, Ca 2ϩ chelator, and channel blockers EGTA, BAPTA, and SK&F96365, as well as K Ca channel blocker iberiotoxin, protein-kinase inhibitors wortmannin and PD 98059, and NF-B inhibitor pyrrolidine dithiocarbamate prevented M&B28767-induced increase in Ca 2ϩ transients and/or eNOS expression in EC nuclei. We describe for the first time that PGE 2 through its access into cell by prostaglandin transporters induces eNOS expression by activating perinuclear EP 3 receptors coupled to pertussis toxin-sensitive G proteins, a process that depends on nuclear envelope K Ca channels, protein kinases, and NF-B; the roles for nuclear EP 3 receptors seem different from those on plasma membrane. (Circ Res. 2002;90:682-689.)

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In frontalized mammals it has been demonstrated that adaptation produces shift of the peak of the orientation tuning curve of neuron following frequent or lengthier presentation of a non-preferred stimulus. Depending on the duration of adaptation the shift is attractive (toward the adapter) or repulsive (away from the adapter). Mouse exhibits a salt-and-pepper cortical organization of orientation maps, hence this species may respond differently to adaptation. To examine this question, we determined the effect of twelve minutes of adaptation to one particular orientation on neuronal orientation tuning curves in V1 of anesthetized mice. Multi-unit activity of neurons in V1 was recorded in a conventional fashion. Cells were stimulated with sine-wave drifting gratings whose orientation tilted in steps. Results revealed that similarly to cats and monkeys, majority of cells shifted their optimal orientation in the direction of the adapter while a small proportion exhibited a repulsive shift. Moreover, initially untuned cells showing poor tuning curves reacted to adaptation by displaying sharp orientation selectivity. It seems that modification of the cellular property following adaptation is a general phenomenon observed in all mammals in spite of the different organization pattern of the visual cortex. This study is of pertinence to comprehend the mechanistic pathways of brain plasticity.