Activated by neurotransmitters, neurotrophic factors and growth factors' the phosphoinositide (Pl) second messenger system is involved in neuronal development, differentiation, survival, and regulation of synapses. The overall goal of this research program has been to elucidate the molecular mechanisms involved in the Pl second messenger system in the brain. In one pathway of the P1 system, receptor stimulated P1 3kinases produce the phosphoinositide messengers Ptdlns(3,4.5)P3 and Ptdlns(3,4)P2. Receptor activated P1 3-lcinaces have been implicated in regulation of cell survival, actin cytoskeletal rearrangements, and vesicular trafficking in the nervous system. But how P1 3-kinases regulate these specific cellular processes has not been resolved. A valuable strategy in elucidating the functions of the Pl messenger system has been the identification and manipulation of the messenger targets. Substantial progress in this arena has led to the identification of phosphoinositide messenger effector proteins including centaurin a. AMP-deaminase and the clathrin adaptor protein AP-2, which are likely participants in neuronal regulation. The novel protein, centaurin a has the specificity, affinity and localization that strongly support its function as a synaptic Ptdlas(3,4,5)P3 effector. Preliminary studies have led to the hypotheses that centaurin a is involved in vesicular trafficking, interacts with the actin cytoskeleton. and is regulated by Ptdlns(3,4,5)P3. Bolstered by the extensive preliminary studies, establishment of a yeast based complementation system, and proposed studies in genetically manipulated embryonic stem cells. These hypotheses concerning the in vivo function of centaurin a, can now be tested. These studies will provide valuable information about the mechanisms by which centaurin a transduces Ptdlus(3.4,5)P3 signals in synaptic development and regulation. A long-term goal is to provide crucial information and useful probes for studies that will facilitate development of therapies for the treatment of neurological disorders and diseases that involve disruption of the Pl system.
| Arnold, Miranda; Cross, Rebecca; Singleton, Kaela S et al. (2016) The Endosome Localized Arf-GAP AGAP1 Modulates Dendritic Spine Morphology Downstream of the Neurodevelopmental Disorder Factor Dysbindin. Front Cell Neurosci 10:218 |
