D₅Dopamine Receptors Mediate Estrogen-Induced Stimulation of Hypothalamic Atrial Natriuretic Factor Neurons

Abstract

Whereas progesterone and dopamine share a common central pathway to modulate sexual behavior in female rats, the way in which estrogen is involved remains unclear. In a long-term rat hypothalamic cell culture system, atrial natriuretic factor-producing neurons were identified as candidate sites for integration of sex steroid action. Estrogen induces the expression of progesterone receptors in atrial natriuretic factor neurons and also augments neuronal functions by increasing expression of constitutively active D5 receptors that generate cAMP in a ligand-independent manner. Such a cross-talk mechanism allows estrogen to exert its effects via the adenylyl cyclase-cAMP system by augmenting dopamine receptor activity, an action that may play an important integrative role in facilitating female sexual behavior.

Insight into the Mechanism of Dopamine D1-like Receptor Activation

“…The D1B receptor distinguishes itself from the D1A subtype by a higher constitutive activity, increased affinity and potency for agonists, decreased affinity for antagonists, and a lower agonist-mediated maximal activation (2). Recently, a study highlighted the potential physiological relevance of the D1B receptor constitutive activity (3). Indeed, the extent of the D1B receptor constitutive activity controls the estrogen-induced mRNA expression of atrial natriuretic factor in primary hypothalamic neurons, a neuroendocrine process that potentially plays a role in D1B receptor-mediated facilitation of female sexual behavior (3).…”

“…Recently, a study highlighted the potential physiological relevance of the D1B receptor constitutive activity (3). Indeed, the extent of the D1B receptor constitutive activity controls the estrogen-induced mRNA expression of atrial natriuretic factor in primary hypothalamic neurons, a neuroendocrine process that potentially plays a role in D1B receptor-mediated facilitation of female sexual behavior (3). Moreover, the detection of D1-like subtype mRNA expression and/or activity in human breast and neuroendocrine gastrointestinal tumor cells (4,5) underscores the importance of these receptors as well as, potentially, their levels of constitutive activation in regulating DA function in pathophysiological conditions, as shown previously with other constitutively active mutant GPCRs (6).…”

“…Nonspecific binding was assessed in the presence of a final concentration of 10 M cis-flupentixol (dissolved in milli-Q-water). For competition studies, frozen membranes were thawed on ice and incubated with a constant concentration of N-[methyl- 3 H]SCH23390 (ϳ0.6 nM) and increasing concentrations of DA in the presence of 0.1 mM ascorbic acid (dissolved in milli-Q-water). Binding assays were incubated for 90 min at room temperature and terminated using rapid filtration through glass fiber filters (GF/C, Whatman).…”