Modulation of the metabotropic glutamate type 2 (mGlu2) receptor is considered a promising target for the treatment of central nervous system diseases such as schizophrenia. Here, we describe the pharmacological properties of the novel mGlu2 receptor positive allosteric modulator (PAM) 3-cyano-1-cyclopropylmethyl-4-(4-phenyl-piperidin-1-yl)-pyridine-2(1H)-one (JNJ-40068782) and its radioligand

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suggest an interaction of GFRα1 and cRET in the absence of GDNF and demonstrate that the high affinity binding can be measured only when cRET is present.

The bioassay-guided fractionation of a dichloromethane extract from the roots of Synaptolepis kirkii using neuronal viability as a model allowed the isolation of the new daphnane orthoester kirkinine (1a) as a powerful neurotrophic constituent.

The molecular mechanisms governing calcium signal transduction of corticotropin-releasing factor (CRF) receptors CRF 1 and CRF 2(a) stably expressed in human embryonic kidney (HEK) 293 cells were investigated. Calcium signaling strictly depended on intracellular calcium sources, and this is the first study to establish a prominent contribution of the three major G-protein families to CRF receptor-mediated calcium signaling. Overexpression of G␣ q/11 and G␣ 16 led to leftward shifts of the agonist concentration-response curves. Blockade of G␣ q/11 proteins by the small interfering RNA (siRNA) technology partially reduced agonist-mediated calcium responses in CRF 1 -and CRF 2(a) -expressing HEK293 cells, thereby proving a contribution of the G q protein family. A small but significant inhibition of calcium signaling was recorded by pharmacological inhibition of G i/o proteins with pertussis toxin treatment. This effect was mediated by direct binding of G␤␥ subunits to phospholipase C. G i/o inhibition also elevated cAMP responses in CRF receptor-overexpressing HEK293 cells and in Y79 retinoblastoma cells endogenously expressing human CRF 1 and CRF 2(a)