CNS Aromatase and Estrogen Receptors: Subcellular Organization and Its Functional Implications

Abstract

Estrogens are known to play an important role in regulation of a myriad of central nervous system (CNS) functions. These include mood, memory, cognition, neuroprotection, and nociception. Estrogen receptors (ERs) and aromatase (aka estrogen synthase) are present not only in reproductive organs, but are also found throughout the CNS. Factors regulating CNS aromatase activity (and thus the availability of locally produced estrogens) are largely unexplored, as are the sources of estrogens impacting CNS functionalities.

Our laboratory recently demonstrated that both aromatase and at least one type of ER, ERα, oligomerizes with aromatase. Furthermore, both ERα and aromatase are present within a multimeric membrane signaling unit. We coined the term ‘oligocrine’ to describe the estrogenic signaling that occurs within the same complex in which the estrogens are produced. This novel form of estrogenic signaling complements the more traditional endocrine relationship between aromatase and ERs.

In this project, I investigated the organizational relationship of CNS aromatase and membrane ERα (mERα), a rapid signaling plasma membrane ER, using co-immunoprecipitation and Western blot analyses. I also explored the regulation of aromatase activity in spinal cord and hypothalamus using the tritiated water release activity assay and the phosphorylation state of the enzyme. I concluded that (1) aromatase and mERα coexist in a membrane complex in two functionally distinct regions of the CNS: spinal cord (predominantly neural) and hypothalamus (neuroendocrine), (2) in spinal cord, aromatase is organized to signal nearly exclusively in oligocrine fashion, whereas in hypothalamus, aromatase is organized to predominantly produce estrogens for export, (3) spinal aromatase activity can be inversely related to circulating estrogen levels, and (4) CNS aromatase activity can be acutely modulated by phosphorylation, independent of genomic regulation.

My studies revealed a remarkable complexity of CNS estrogenic signaling. Results offer a glimpse into how CNS estrogenic signaling is segregated on subcellular as well as regional levels in a functionality-dependent manner. Observations could also explain how some estrogen-dependent CNS functionalities peak in-phase, while others peak out-of-phase with circulating estrogens, underscoring the imperative to include not only sex, but also stage of menstrual cycle as a biological variable when designing clinical trials targeting estrogen-dependent CNS functionalities. Finally, developing therapeutic approaches that target specific subcellular populations of aromatase and ERα could selectively facilitate restoration of impaired estrogen-dependent CNS functionalities while limiting undesirable effects.