Cardiotonic steroid ouabain stimulates steroidogenesis in Leydig cells via the α3 isoform of the sodium pump. Issue 191 (July 2019)

• Record Type: Journal Article
• Authors: Upmanyu, Neha; Dietze, Raimund; Bulldan, Ahmed; Scheiner-Bobis, Georgios
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 191(2019)
• Publication Date: 2019-07
• Subjects: Sodium pump -- Leydig cells -- Ouabain -- Lipid droplet -- Perilipin -- Steroidogenesis; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2019.04.021
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: We demonstrate hormone-like actions of ouabain on a Leydig cell line. We show ouabain-induced activation of Erk1/2, CREB and ATF-1. Ouabain triggers mobilization of LDs and PLIN2 and stimulates steroidogenesis. Silencing expression of the α3 isoform of the sodium pump prevents all the above. The results imply that ouabain-induced signaling might be part of male physiology. Abstract: Cardiotonic steroids such as ouabain are potent inhibitors of the sodium pump and have been widely used for centuries in the treatment of congestive heart failure. In recent decades, however, they have also been identified as hormone-like molecules that trigger signaling cascades of physiological relevance by using the various sodium pump α subunit isoforms as receptors. The murine Leydig cell line MLTC-1 expresses both the ubiquitous, relatively ouabain-insensitive α1 isoform of the sodium pump and the ouabain-sensitive α3 isoform that is normally found in neuronal cells. The physiological relevance of the simultaneous presence of the two isoforms in Leydig cells has not been previously addressed. MLTC-1 Leydig cells contain lipid droplets (LDs) and are capable of progesterone biosynthesis when stimulated by luteinizing hormone (LH). When exposed to low nanomolar concentrations of ouabain, they respond with stimulation of Erk1/2, CREB, and ATF-1 phosphorylation, LD enlargement, and perilipin2 mobilization to the LDs. As a result, progesterone biosynthesis is augmented. Abrogation of α3 isoform expression by siRNA prevents all of the above responses, indicating that it is the hormone/receptor-like interaction of ouabain exclusively with this isoform that triggers the signaling events that normally occur when LH binds to its receptor. Considering that ouabain is produced endogenously and is found in seminal fluid, one can speculate that effects of this substance on germ and somatic cells of the testis might play a role in male reproductive physiology.