Sigma-1 Receptor Ligands Interact with the Outer Mitochondrial Membrane and Facilitate Cholesterol Transport into the Mitochondria for Steroid Hormone Synthesis

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 355-388-Sex Hormone Receptor Action & Reaction
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-387
Karla-Sue C Marriott*1, Manoj Prasad2, Veena Thapliyal3 and Himangshu S Bose4
1Savannah State University, Savannah, GA, 2Mercer University, Savannah, GA, 3Mercer University School of Medicine, Savannah, GA, 4Mercer Univ Schl of Med, Savannah, GA
The Mitochondria-Associated ER-Membrane (MAM) is a small section of the outer mitochondrial membrane (OMM) tethered to the endoplasmic reticulum by lipid and protein filaments. One such MAM protein is sigma-1 receptor, which contributes to multiple signaling pathways. We found that siRNA1-mediated knockdown of sigma-1 reduced progesterone synthesis by 75% without affecting expression of inner mitochondrial membrane (IMM) resident enzyme 3-beta hydroxysteroid dehydrogenase2 (3βHSD2). To explore the underlying mechanism of this effect, we generated a series of sigma-1 ligands that included KSCM-1, KSCM-5 and KSCM-11.  All three specifically bound to sigma-1 in the nanomolar range while KSCM-5 and KSCM-11 also bound to sigma-2.  Treatment of cells with KSCM ligands led to decrease cell viability, with KSCM-5 having the most potent effect followed by KSCM-11.  KSCM-1 increased both expression of sigma-1 by four-fold and progesterone synthesis, whereas the other compounds decreased progesterone.   These differences likely are due to compound structure: For example KSCM-1 has two methoxy substituents at C-5 and C-6 of the benzofuran ring while KSCM-11 has one at C-6.  KSCM compounds or sigma-1 knockdown did not alter expression of ER (Endoplasmic Reticulum) resident enzymes that synthesize steroids. However, coimmunoprecipitation of the sigma-1 receptor pulled down voltage-dependent anion channel2 (VDAC2), whose expression was enhanced by KSCM-1.   This VDAC plays a key role in substrate transport into the mitochondria, suggesting that the sigma-1 receptor at MAM contributes to the transfer of substrate from the ER to mitochondria for steroid synthesis.

Nothing to Disclose: KSCM, MP, VT, HSB

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Sources of Research Support: NIH