NOVEL SECOND MESSENGER SIGNALING IN THE STRIATUM

Massachusetts Institute Of Technology, Cambridge MA

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Abstract

Ras proteins are key regulators of growth and differentiation, but recently have also been implicated in learning and memory functions in the brain. Rap proteins inhibit Ras signaling through the MAP kinase pathway or, via B-Raf, also can activate MAP kinase. Thus Rap and Ras proteins may have antagonistic or complementary functions in cells. Guanine nucleotide exchange factors (GEFs) can activate Rap and Ras proteins. Many Ras GEFs, but until the work described, only Rap GEF, have been identified. We have discovered new families of brain-enriched genes that code for Ras-superfamily GEFs and second messenger binding motifs. We proposed to concentrate on the calcium and diacylglycerol- regulated GEFs, CalDAG-GEFs, which are highly enriched in the striatum. We have found that CalDAG-GEFI activates Rap1, whereas CalDAG-GEFII activates Ras, as also reported by Ebinu et al., 1998. Ca2+ and DAG both augment this activation. CalDAG-GEFI and CalDAG-GEFII are both strong expressed in the projection neurons of the striatum and they co-exist in many if not most of these neurons. This co-expression may provide a mechanism by which calcium and DAG signaling can be coordinated or switched from Rap1 to Ras activation, depending on the CalDAG-GEF engaged. Ras is involved in the neuroplasticity underlying learning and memory, and we hypothesize that Rap1 may be as well. To test this broad hypothesis, we propose to examine the CalDAG-GEFs in cellular and systems-level experiments using binding assays, mutational genetic approaches, distribution and cellular localization studies, assays for CalDAG-GEFI and II coupling to glutamate and dopamine neurotransmitter systems, and tests of learning and memory and other neurologic function in transgenic and knockout mice lacking CalDAG-GEF function. The health- related significance of this work rests in the fact that the second messenger molecules for which the novel proteins have binding motifs are essential for normal brain function and for plasticity and memory. Understanding these novel second messenger signaling molecules will therefore bring insights to understanding fundamentally important brain functions and will help in elucidating brain disorders.