HZF-3, an immediate-early orphan receptor homologous to NURR1/NOT: Induction upon membrane depolarization and seizures

Nuclear hormone receptors are thought to play important roles in the regulation of gene expression in the hippocampus. We report here the isolation of an additional member of this superfamily, HZF-3, which is expressed preferentially in the rat brain and therein within the hippocampus. HZF-3 cDNA encodes a 66.6-kDa protein with high homology to the inducible nuclear orphan receptors NURR1/NOT and NGFI-B. Like NURR1/NOT and NGFI-B, HZF-3 mRNA accumulates in PC12 cells subsequent to membrane depolarization. In the rat brain, HZF-3 expression is induced following seizures elicited by the chlorinated insecticide lindane. The time course of HZF-3 induction by membrane depolarization in PC12 cells and seizures in animals is more prolonged than that observed for other immediate-early genes, such as NGFI-B. Electrophoretic mobility shift assays demonstrated HZF-3 to interact specifically with the same DNA target element as NGFI-B: NBRE. These results suggest HZF-3 is a member of a distinct family of inducible orphan receptors which are likely to display synergistic and/or antagonistic regulatory functions in mediating signal-induced transcriptional responses in the nervous system.