Figure 1. Presynaptic actions of 17β-estradiol (E2) in POMC neurons.

Schematic overview of the E2-mediated modulation of Gαi,o-coupled GABA_B receptors via a membrane-associated receptor (mER) in hypothalamic POMC nerve terminals. E2 binds to a mER that is Gαq-coupled to activate phospholipase C and catalyzes the hydrolysis of membrane-bound phosphatidylinositol 4,5-biphosphate (PIP₂) to inositol 1,4,5 triphosphate (IP₃) and diacylglycerol (DAG). Calcium is released from intracellular stores (endoplasmic reticulum) by IP₃, and DAG activates protein kinase C Δ (PKCΔ). Through phosphorylation, adenylyl cyclase VII (AC VII) activity is upregulated by PKC. The generation of cAMP activates PKA, which can uncouple (dashed line) GABA_B receptors from their signaling pathway through phosphorylation of a downstream effector molecule (e.g., G protein-coupled, inwardly rectifying K⁺, GIRK, channels). Together, elevated intracellular Ca²⁺ and attenuation of GABA_B-mediated inhibition will facilitate the release of multiple neurotransmitters—GABA, glutamate, β-endorphin and α-melanocyte stimulating hormone (α-MSH)—from POMC neurons.