Transmembrane signaling through phospholipase C-beta in the developing human prefrontal cortex.

Abstract

To investigate changes in muscarinic receptor-stimulated phospholipase C-beta (PLC-beta) activity during brain development, we examined the functional coupling of each of the three major protein components of the phosphoinositide system (M1, M3, and M5 muscarinic receptor subtypes; Gq/11 proteins; PLC-beta1-4 isoforms) in membrane preparations from post-mortem human prefrontal cerebral cortex collected at several stages of prenatal and postnatal development. In human prenatal brain membranes, PLC was found to be present and could be activated by calcium, but the ability of guanosine-5'-o-3 thiotriphosphate (GTPgammaS) or carbachol (in the presence of GTPgammaS) to modulate prenatal PLC-beta was significantly weaker than that associated with postnatal PLC-beta. Western blot analysis revealed that the levels of Galphaq/11 did not change significantly during development. In contrast, dramatically higher levels of expression of PLC-beta1-4 isoforms and of M1, M3, and M5 muscarinic receptors were detected in the child vs. the fetal brain, a finding that might underlie the observed increased activity of PLC. Thus, inositol phosphate production may be more efficiently regulated by altering the amount of effectors (PLC-beta1-4) and receptors (M1,3,5 subtypes) than by altering the level of Galphaq/11 subunits. These results demonstrate that different PLC isoforms are expressed in the prefrontal cortex of the developing human brain in an age-specific manner, suggesting specific roles not only in synaptic transmission but also in the differentiation and maturation of neurons in the developing brain.