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.

Orally applied doxazosin disturbed testosterone homeostasis and changed the transcriptional profile of steroidogenic machinery, cAMP/cGMP signalling and adrenergic receptors in Leydig cells of adult rats

“…LH/hCG receptors activation leads to stimulation of adenylyl cyclase (ADCY), accumulation in cAMP and activation of the cAMP-dependent kinase (PRKA). The phosphodiesterases (PDEs) terminate cAMP/cGMP signalling and have regulatory function in Leydig cells (Catt & Dufau, 1973;Dufau, 1998;Tsai & Beavo, 2011). No.337, …”

“…Considering the importance of cAMP-PRKA signalling pathway for steroidogenesis (reviewed in Dufau, 1998;Hansson et al, 2000;Payne & Hales, 2004;Tsai & Beavo, 2011, the real time PCR analysis for elements of this signalling in Leydig cells from control and Doxa-treated rats was performed by using the specific primers (see Table S2 in the Supplemental Materials and methods).…”

“…Considering the importance of 'cross talk' between cAMP and cGMP signalling pathways for cell homeostasis and the role of cGMP-PRKG-PDE signalling in steroidogenesis (reviewed in Tsai & Beavo, 2011), the real time PCR analysis for elements of NOcGMP signalling in Leydig cells from control and Doxa-treated rats was performed by using the specific primers (see Table S3 in the Supplemental Materials and methods).…”

“…LH/hCG receptors activation (Zhang & Dufau, 2003) leads to stimulation of adenylyl cyclase (ADCY), accumulation in cAMP and activation of the cAMP-dependent kinase (PRKA). The phosphodiesterases (PDEs) terminate cAMP/ cGMP signalling and have regulatory function in Leydig cells (Catt & Dufau, 1973;Dufau, 1998;Tsai & Beavo, 2011. Although Leydig cell steroidogenesis is mainly activated through LH/hCG receptors, regulation itself is a multi-compartmental process and includes neural (Selvage et al, 2006) and complex endocrine, paracrine and autocrine signalling pathways (reviewed in Saez, 1994;Gnessi et al, 1997;Payne & Hales, 2004) including cGMP (Andric et al, 2010a,b) and adrenergic signalling (Anakwe et al, 1985).…”

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

“…In particular, the intracellular concentration of cAMP is partly determined by (1) a balance between AC activation through the GTP-binding protein Gs and inhibition through the GTP-binding inhibitory protein Gi (Hausdorff et al 1987, Begeot et al 1988, Hausdorff et al 1989; and (2) several isoforms of ACs (AC5/6, insensitive to Ca 2+ , AC3, activated by Ca 2+ , and AC4, activated by the βγ subunits of G proteins) (Shen et al 1997, Côté et al 2001. Studies of gene expression of the rat ZG indeed showed that AC3 and AC4 are selectively enriched in ZG (Nishimoto et al 2013); (3) several isoforms of phosphodiesterases (PDEs), in particular cGMP-PDE2 (the highest concentrations being found in the ZG (McFarlane & Sowers 2003)) and PDE8, important in regulating corticosterone secretion in ZF cells (Tsai & Beavo 2011).…”