Estrogen Receptor Involvement in Noradrenergic Regulation of Ventromedial Hypothalamic Nucleus Glucoregulatory Neurotransmitter and Stimulus-Specific Glycogen Phosphorylase Enzyme Isoform Expression

Abstract

Norepinephrine (NE) directly regulates ventromedial hypothalamic nucleus (VMN) glucoregulatory neurons and also controls glycogen-derived fuel provision to those cells. VMN nitric oxide (NO) and γ-aminobutyric acid (GABA) neurons and astrocytes express estrogen receptor-alpha (ERα) and ER-beta (ERβ) proteins. Current research used selective ERα (1,3Bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride) or ERβ (4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol) antagonists to address the premise that these ERs govern basal and/or NE-associated patterns of VMN metabolic neuron signaling and astrocyte glycogen metabolism. Both ERs stimulate expression of the enzyme marker protein neuronal nitric oxide synthase, not glutamate decarboxylase_65/67. NE inhibition or augmentation of neuronal nitric oxide synthase and glutamate decarboxylase_65/67 profiles was ER-independent or -dependent, respectively. In both neuron types, VMN ERβ activity inhibited baseline alpha1- (α₁-) and/or alpha2- (α₂-)adrenergic receptor (AR) expression, but ERα and -β signaling was paradoxically crucial for noradrenergic upregulation of α₂-AR. NE inhibited glycogen synthase expression and exerted opposite effects on VMN adenosine monophosphate-sensitive glycogen phosphorylase (GP)-brain type (stimulatory) versus NE-sensitive GP muscle (inhibitory) via ERα or -β activity. Results document unique ERα and ERβ actions on metabolic transmitter and AR protein expression in VMN nitrergic versus GABAergic neurons. ER effects varied in the presence versus absence of NE, indicating that both neuron types are substrates for estradiol and noradrenergic regulatory interaction. NE-dependent ER control of VMN GP variant expression implies that these signals also act on astrocytes to direct physiological stimulus-specific control of glycogen metabolism, which may in turn influence GABA transmission.

Keywords: alpha-adrenergic receptor; estrogen receptor; glutamate decarboxylase; nitric oxide synthase; norepinephrine; ventromedial hypothalamic nucleus.