Two different patterns of neurotransmitter activation of phosphoinositide phospholipase C (PLC) exist in brain tissue. The first corresponds to a direct G protein mediated activation and is elicited by muscarinic agonists and serotonin, whereas the second, probably indirect and secondary to extracellular calcium entry, results from stimulation by noradrenaline, histamine, glutamate and endothelin-1. Furthermore, these four neurotransmitters but not acetylcholine or serotonin activate phospholipase D (PLD) in the same tissue, suggesting the occurrence of common mechanisms in the activation of both phospholipases by these agonists. In this project we propose to investigate the relationship between the patterns of PLC activation by agonists and their ability to stimulate PLD extending the study to the purinergic receptors as well as to receptors of several neuroactive peptides that also mediate PLC activation by agonists and their ability to stimulate PLD extending the study to the purinergic recptors as well as to receptors of several neuroactive peptides that also mediat PLC activation in nervous tissue. We also propose to study the pathaways of PLD activation in brain tissue, analyzing the role of calcium and the involvement of protein kinase C, tyrosine kinase activities and G proteins . in this latter case we will investigate the involvement of the mononomeric G proteins and the actions of the G protein beta-gamma subunits. Finally, the involvement of teh different pathaways of PLD activation in the agonists effect will be examined as well as their link to the mechanisms involved in the activation of phosphoinositide hydrolisis, including the role of phosphatidylinositol 4,5-biophosphate as a putative cofactor of PLD.
|Effective start/end date||1/07/95 → 1/07/98|