SummarySensing the level of oxygen in the external and internal environments is essential for survival. Organisms have evolved multiple mechanisms to sense oxygen. No function in oxygen sensing has been attributed to any mammalian olfactory system. Here, we demonstrate that low environmental oxygen directly activates a subpopulation of sensory neurons in the mouse main olfactory epithelium. These neurons express the soluble guanylate cyclase Gucy1b2 and the cation channel Trpc2. Low oxygen induces calcium influx in these neurons, and Gucy1b2 and Trpc2 are required for these responses. In vivo exposure of a mouse to low environmental oxygen causes Gucy1b2-dependent activation of olfactory bulb neurons in the vicinity of the glomeruli formed by axons of Gucy1b2+ sensory neurons. Low environmental oxygen also induces conditioned place aversion, for which Gucy1b2 and Trpc2 are required. We propose that this chemosensory function enables a mouse to rapidly assess the oxygen level in the external environment.

Dopamine neurons of the hypothalamic arcuate nucleus (ARC) tonically inhibit the release of the protein hormone prolactin from lactotropic cells in the anterior pituitary gland and thus play a central role in prolactin homeostasis of the body. Prolactin, in turn, orchestrates numerous important biological functions such as maternal behavior, reproduction, and sexual arousal. Here, we identify the canonical transient receptor potential channel Trpc5 as an essential requirement for normal function of dopamine ARC neurons and prolactin homeostasis. By analyzing female mice carrying targeted mutations in the Trpc5 gene including a conditional Trpc5 deletion, we show that Trpc5 is required for maintaining highly stereotyped infraslow membrane potential oscillations of dopamine ARC neurons. Trpc5 is also required for eliciting prolactin-evoked tonic plateau potentials in these neurons that are part of a regulatory feedback circuit. Trpc5 mutant females show severe prolactin deficiency or hypoprolactinemia that is associated with irregular reproductive cyclicity, gonadotropin imbalance, and impaired reproductive capabilities. These results reveal a previously unknown role for the cation channel Trpc5 in prolactin homeostasis of female mice and provide strategies to explore the genetic basis of reproductive disorders and other malfunctions associated with defective prolactin regulation in humans.

#3033 Background 
 Case-control studies have reported inconsistent results concerning breast cancer risk and polymorphisms in genes that control endogenous estrogen biosynthesis. We report findings from the first study in Mexican women examining associations between female with breast cancer and polymorphisms CYP19 (TTTA repeated polymorphism).
 Methods 
 We conducted a study among 180 healthy women and 70 women with breast cancer underwent hormone therapy with aromatase inhibitor. DNA and questionnaire data was obtained. Tandem repeated (TTTA)n polymorphism in CYP19 gene was determined by PCR followed by electrophoresis on denaturalizing acrilamide gel stained with silver nitrate. Differences were visualized with Gel-Doc BioRad. Estrone, estradiol and FSH levels were measured by RIA and IRMA. We used likelihood-based statistical methods to examine allelic associations.
 Results:
 250 women (age 55 ± 12 years) were included. BMI was 30 ± 7.1 Kg/m2. We found a distribution of different CYP19 allele frequencies. In healthy women the allele frequencies with 6 (32.7 %) and 7 (21.6 %) tandem repetitions were the most frequent, in women with breast cancer the alleles with 6(29%) and 10(26%) tandem repeated were the most frequent. A relationship between hormonal levels and number of (TTTA) repeated was not found. Anastrozol reduced significantly estrona and estradiol. Surpriseling we found in a patients with 10 or more (TTTA)n repeated an association with a mayor tumoral activity (p=0.04).
 Conclusion 
 This study indicates that status of CYP19 >10 TTTA repeated might be related to increased breast cancer risk and with the clinical response (aromatase inhibitor). Because of this is the first study to report an association between CYP19 >10 TTTA repeated and treatment hormonal response in breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3033.