Peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator 1␣ (PGC-1␣) is a transcriptional coactivator that is a key component in the regulation of energy production and utilization in metabolic tissues. Recent work has identified PGC-1␣ as a strong coactivator of the orphan nuclear receptor estrogen-related receptor ␣ (ERR␣), implicating ERR␣ as a potential mediator of PGC-1␣ action. To understand the role of ERR␣ in PGC-1␣ signaling, a parallel approach of high-throughput screening and gene-expression analysis was used to identify ERR␣ small-molecule regulators and target genes. We report here the identification of a potent and selective ERR␣ inverse agonist that interferes effectively with PGC-1␣͞ERR␣-dependent signaling. This inverse agonist inhibits the constitutive activity of ERR␣ in both biochemical and cell-based assays. Also, we demonstrate that monoamine oxidase B is an ERR␣ target gene whose expression is regulated by PGC-1␣ and ERR␣ and inhibited by the ERR␣ inverse agonist. The discovery of potent and selective ERR␣ modulators and their effect on PGC-1␣ signaling provides mechanistic insight into gene regulation by PGC-1␣. These findings validate ERR␣ as a promising therapeutic target in the treatment of metabolic disorders, including diabetes and obesity.

Neuregulin (NRG), a growth and differentiation factor that signals via erbB receptor tyrosine kinases, has been shown to have biological effects in both the CNS and the peripheral nervous system. We report here that erbB4 is expressed in mature cerebellar granule cells, where it appears to be concentrated at the granule cell postsynaptic terminals. We also show that one form of NRG, Ig-NRG, plays a crucial role in aspects of cerebellar granule cell development in vitro. First, Ig-NRG treatment of granule cells in culture selectively induces the expression of the GABA(A) receptor beta2 subunit. This increase in subunit expression is paralleled by an increase in functional GABA(A) receptors. In contrast to its effects on GABA(A) receptor subunit expression, Ig-NRG does not upregulate NMDA receptor N2B and N2C subunit expression. Second, we demonstrate that Ig-NRG also enhances neurite outgrowth from cultured granule cells. Ig-NRG does not, however, act as a survival factor for the granule cells. We have compared the effect of Ig-NRG with the effects of brain-derived neurotrophic factor (BDNF), a neurotrophin that exerts specific effects on granule cells in culture, and found that BDNF does not mimic the effects of Ig-NRG on GABA(A) receptor subunit expression. Our results show that Ig-NRG has specific effects on granule cell development and maturation and may regulate these processes in vivo.

The estrogen-related receptor alpha (ERRalpha) is an orphan receptor belonging to the nuclear receptor superfamily. The physiological role of ERRalpha has yet to be established primarily because of lack of a natural ligand. Herein, we describe the discovery of the first potent and selective inverse agonist of ERRalpha. Through in vitro and in vivo studies, these ligands will elucidate the endocrine signaling pathways mediated by ERRalpha including association with human disease states.

Rats on a chronic intermittent ethanol (CIE) regimen showed a persistent reduction in seizure threshold to the convulsant drug pentylenetetrazol (PTZ). CIE rats were given ethanol by intubation on an alternate day schedule and tested at selected intervals for seizure threshold with PTZ. A significant reduction in seizure threshold, a sign of withdrawal, was observed 20 hr after the first dose. The severity of withdrawal intensified on repetition of the ethanol administration and depression-hyperexcitability cycle, with the seizure threshold reaching a maximum decrease after 12 doses and remaining reduced up to 60 doses. The reduction in seizure threshold persisted for at least 40 days of no alcohol following the 60th dose. The long-lasting decrease in seizure threshold following CIE treatment resembled the "kindling" phenomenon produced by chronic administration of PTZ (25 mg/kg, 3 times/week). The CIE rats developed, in addition, a tolerance to the anticonvulsant action of ethanol, which occurred well after the decrease in PTZ seizure threshold, and a tolerance to the hypothermic effect of ethanol, which developed rapidly. PTZ kindled rats that had never been exposed to ethanol also exhibited tolerance to the hypothermic effect of ethanol. We propose that kindling contributes to the mechanism of the development of dependence on central nervous system depressants like benzodiazepines, barbiturates, and alcohol, drugs that act on the gamma-aminobutyric acid-A receptor chloride ion channel complex. Repeated episodes of depression and withdrawal hyperexcitability are postulated to produce kindling during the repeated withdrawal episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

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