Guanine nucleotide exchange factors CalDAG-GEFI and CalDAG-GEFII are colocalized in striatal projection neurons.

CalDAG-GEFI and CalDAG-GEFII (identical to RasGRP) are novel, brain-enriched guanine nucleotide exchange factors (GEFs) that can be stimulated by calcium and diacylglycerol and that can activate small GTPases, including Ras and Rap1, molecules increasingly recognized as having signaling functions in neurons. Here, we show that CalDAG-GEFI and CalDAG-GEFII mRNAs, detected by in situ hybridization analysis, have sharply contrasting forebrain-predominant distributions in the mature brain: CalDAG-GEFI is expressed mainly in the striatum and olfactory structures and deep cortical layers, whereas CalDAG-GEFII is expressed widely in the forebrain. Within the striatum, however, the two CalDAG-GEF mRNAs have nearly identical distributions: they are coexpressed in striatal projection neurons that give rise to the direct and indirect pathways of the basal ganglia. Subcellular fractionation analysis of the substantia nigra with monoclonal antibodies against CalDAG-GEFI suggests that CalDAG-GEFI protein is present not only in the cell bodies of striatal projection neurons but also in their axons and axon terminals. These results suggest that the CalDAG-GEFs may be key intracellular regulators whereby calcium and diacylglycerol signals can regulate cellular functions through small GTPases in the basal ganglia circuits.