The roles of cyclic nucleotide phosphodiesterases (PDEs) in steroidogenesis

Abstract

The second messenger, cAMP, is one of the most important regulatory signals for control of steroidogenesis. This review focuses on current knowledge about regulation of cyclic nucleotides by phosphodiesterases (PDEs) in steroidogenic tissues. The first PDE known to directly regulate steroidogenesis was PDE2, the cGMP-stimulated PDE. PDE2 mediates ANP/cGMP-induced decreases in aldosterone production. Recently, the PDE8 family has been shown to control steroidogenesis in two tissues. Specifically, PDE8A regulates testosterone production by itself and in concert with additional IBMX-sensitive PDEs. PDE8B modulates basal corticosterone synthesis via acute and chronic mechanisms. In addition to cAMP-dependent pathways, cGMP signaling also can promote steroidogenesis, and PDE5 modulates this process. Finally, PDE mutations may lead to several human diseases characterized by abnormal steroid levels.

Figure 1. PDE regulation of sterodogenesis

Steroidogenic cell types respond to pituitary hormones, such as ACTH and LH. Upon binding to these G_αs-protein coupled receptors, cAMP is synthesized by adenylyl cyclase (AC) from ATP. The cAMP/PKA pathway then promotes steroidogenesis via acute PKA activation and long-term activation of cAMP-dependent transcription. The low K_m and low V_max PDE8 family is shown to modulate this pool of cAMP under basal to minimally stimulated conditions. Other IBMX-sensitive PDEs, like PDE4, modulate cAMP when cells are more highly stimulated. Additionally, the cGMP/PKG pathway also promotes steroidogenesis in some cell types, such as Leydig cells. PDE5 is reported to modulate this pool of cGMP in Leydig cells. However, in adrenal glomerulosa cells cGMP attenuates aldosterone production via activation of PDE2A. PDE2A, also known as cGMP-stimulated PDE, attenuates steroid production via increasing cAMP hydrolysis upon atrial natriueretic peptide (ANP) activation of guanylyl cyclase (GC).

Figure 2. The effects of PDE inhibitors on steroid production

Isolated primary mouse adrenal cells were used to establish this ACTH dose-response curve. In all conditions, the conversion of pregnenolone to progesterone is blocked by 10 μM trilostane (a 3βHSD inhibitor). Therefore, pregnenolone secreted into the culture media is a reflection of the initial steps of steroid production. The same preparation of adrenal cells was pretreated for 30 min with vehicle, 50 μM pan-PDE inhibitor IBMX, 100 nM PDE8-selective inhibitor PF-04957325, or a combination of both PDE8 and pan-PDE inhibitors. All data points were normalized to vehicle treated maximum pregnenolone as 100%, and curves were drawn using the sigmoidal dose-response fit on Graphpad Prism®. Under basal and submaximal stimulated conditions, PDE8 inhibition significantly potentiates pregnenolone production while IBMX treatment is less effective. However, IBMX treatment increases pregnenolone production most effectively under higher ACTH-stimulation. Furthermore, under all conditions inhibition of PDE8 plus at least one other IBMX-sensitive PDE is necessary to achieve maximum steroidogenesis.