Endocrinology & Metabolic Syndrome
Open Access
ISSN: 2161-1017
+44 1478 350008
ISSN: 2161-1017
+44 1478 350008
Joe Beavo, Masami Shimizu, Martin Golkowski, Danny Shen and Shao-En Ong
University of Washington School of Medicine, USA
Posters-Accepted Abstracts: Endocrinol Metab Syndr
Hormones that stimulate Gs-coupled adenylyl cyclase (AC) are major stimulators of steroid production in the ovary, adrenal gland and testis. Since elevated cAMP levels can stimulate steroid production more than 100 fold, it is likely that cAMP is the principle second messenger regulator of steroid hormone production in the body. The levels of cAMP are controlled not only by ACs but also by cAMP phosphodiesterases (PDEs) and PDE inhibitors can be potent stimulators of steroid output. However, to elicit maximum steroid output, more than one PDE must be inhibited. Mechanistically, current data suggest that most of the effects of cAMP and PDE inhibition in steroidogenic cells are mediated via activation of cAMP-dependent protein kinases (PKAs). In an effort to explain at a molecular level how synergy between PDE inhibitors can occur and also to explore the molecular mechanism by which PKA can stimulate steroid production, our laboratories are utilizing a phosphoproteomic analysis of MA10 Leydig cells stimulated by various combinations of PDE inhibitors. We find a rather large number of cAMP/PKA consensus phosphorylation sequences (>200) that are increased by the PDE inhibitor combination. Nearly all of these are known or suggested to be involved in processes that would be expected to increase cholesterol substrate availability to the mitochondria. Therefore, the data suggests that cAMP/PKA acts to coordinate a large increase in steroid production by modulating many different metabolic regulatory pathways, all of which contribute to increasing the availability of free cholesterol at the mitochondrial outer membrane.
Email: beavo@u.washington.edu