Membrane and nuclear initiated estrogenic regulation of homeostasis

Abstract

Reproduction and energy balance are inextricably linked in order to optimize the evolutionary fitness of an organism. With insufficient or excessive energy stores a female is liable to suffer complications during pregnancy and produce unhealthy or obesity-prone offspring. The quintessential function of the hypothalamus is to act as a bridge between the endocrine and nervous systems, coordinating fertility and autonomic functions. Across the female reproductive cycle various motivations wax and wane, following levels of ovarian hormones. Estrogens, more specifically 17β-estradiol (E2), coordinate a triumvirate of hypothalamic neurons within the arcuate nucleus (ARH) that govern the physiological underpinnings of these behavioral dynamics. Arising from a common progenitor pool of cells, this triumvirate is composed of the kisspeptin (Kiss1^ARH), proopiomelanocortin (POMC), and neuropeptide Y/agouti-related peptide (AgRP) neurons. Although the excitability of these neuronal subpopulations is subject to genomic and rapid estrogenic regulation, kisspeptin neurons are the most sensitive, reflecting their integral function in female fertility. Based on the premise that E2 coordinates autonomic functions around reproduction, we will review the recent findings on the synaptic interactions between Kiss1, AgRP and POMC neurons and how the rapid membrane-initiated and intracellular signaling cascades activated by E2 in these neurons are critical for control of homeostatic functions supporting reproduction.

Keywords: Hypothalamus; Kisspeptin neurons; Neuropeptide Y/agouti-related peptide neurons; Peptides; Proopiomelanocortin neurons; Synaptic transmission.

Figure 1.

Circuit diagram of neurons of the arcuate nucleus of the hypothalamus. Fasted State (left panel): When a female experiences an energy deficit, AgRP neurons become highly active and release GABA onto Kiss1 and POMC neurons, inhibiting fertility and satiety. Fed State (right panel): When the female is fed and/or in a high 17β-estradiol state (e.g., proestrus), AgRP neurons become less active and their inhibitory input onto Kiss1 and POMC neurons is diminished. Concurrently, the probability of glutamate release is enhanced in both Kiss1 and POMC neurons. While glutamate released onto AgRP neurons will activate excitatory α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, the influence will be an overall inhibitory effect through Group II/III metabotropic glutamate channels. Conversely, POMC neurons express excitatory Group I metabotropic glutamate receptors and their increased activity may cause the release of neuropeptides such as β-endorphin, which will further inhibit AgRP neurons, decreasing food intake. POMC neurons also excite Kiss1 neurons via glutamate release.

Figure 2.

E2 and insulin signaling cascades in POMC neurons. Insulin through its cognate receptor can activate phospholipase C (PLCγ) to cleave Phosphotidylinositol 4,5 biphosphate (PIP₂) into Diacylglycerol (DAG) and Inositol triphosphate (IP₃) opening TRPC5 channels and generating an inward cationic current to depolarize POMC neurons. Binding of E2 to Gαq-coupled mERs activates phospholipase C (PLCβ) – protein kinase C (PKCδ) – adenylyl cyclase (ACVII) – protein kinase A (PKA) signaling cascade to decouple GABA_B (and μ-opioid) receptors from inhibitory G protein-coupled inwardly rectifying K⁺(GIRK) channels. PKA can also phosphorylate cAMP response element binding protein (pCREB) to generate new gene transcription through CRE’s. In addition, E2 binds to estrogen receptor α (ERα) in POMC neurons to increase Pomc, Vglut2, TRPC5 and CaV3.1 gene expression through ERE’s. On the other hand, stromal interacting molecule 1 (Stim1) expression is decreased, preserving TRPC5 channels as receptor operated channels for transmitting insulin’s (and leptin’s) effects. Note: E2 has similar actions in kisspeptin neurons with the exception that E2 downregulates the expression of the peptide.