Estrogen signaling in hypothalamic circuits controlling reproduction

Abstract

It is well known that many of the actions of 17β-estradiol (E2) in the central nervous system are mediated via intracellular receptor/transcription factors that interact with steroid response elements on target genes. However, there is compelling evidence for membrane steroid receptors for estrogen in hypothalamic and other brain neurons. Yet, it is not well understood how estrogen signals via membrane receptors and how these signals impact not only membrane excitability but also gene transcription in neurons that modulate GnRH neuronal excitability. Indeed, it has been known for some time that E2 can rapidly alter neuronal activity within seconds, indicating that some cellular effects can occur via membrane delimited events. In addition, E2 can affect second messenger systems including calcium mobilization and a plethora of kinases to alter cell signaling. Therefore, this review will consider our current knowledge of rapid membrane-initiated and intracellular signaling by E2 in hypothalamic neurons critical for reproductive function.

Figure 1. Cross-talk between estrogen and leptin signaling in POMC neurons

Through a putative GPCR (mER), E2 (and STX) activates a PLCβ-PKCδ-AC-PKA pathway in POMC neurons that attenuates the coupling of μ-opioid and GABA_B receptors to GIRK channels (heterologous desensitization) and triggers the release of Ca²⁺ from intracellular stores. This novel pathway also activates PKA-pCREB mediated transcription and in tandem with ERE-mediated transcription will alter the mRNA expression of relevant genes (channels and signaling molecules, etc.). Leptin binds to LRb to activate PI3 kinase and PLCγ1 to augment TRPC-channel currents and POMC neuronal excitability. Leptin will also activate JAK2-STAT3 transcriptional pathways. Note: The guinea pig, similar to the primate, has all of the key cellular elements in the mediobasal hypothalamus for controlling reproduction and energy homeostasis.