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Mitochondrial A-Kinase Anchoring Protein 121 Binds Type II Protein Kinase A and Enhances Steroidogenic Acute Regulatory Protein-Mediated Steroidogenesis in MA-10 Mouse Leydig Tumor Cells

Abstract
The expression of the steroidogenic acute regulatory protein (STAR) is regulated by PKA in response to trophic hormone stimulation through the second messenger cAMP. However, in steroidogenic cells the levels of hormone necessary to maximally induce cAMP synthesis and PKA activity are often significantly higher than is necessary to achieve maximum steroidogenesis. One general mechanism considered to make PKA signaling more effective is the utilization of A-kinase anchoring proteins (AKAPs) to recruit PKA to discrete subcellular compartments, which coordinates and focuses PKA action with respect to its substrates. The characterization of A-kinase anchoring protein 121 (AKAP121) has suggested that it may enhance the post-transcriptional regulation of STAR by recruiting both Star mRNA and PKA to the mitochondria, thereby permitting more effective translation and phosphorylation of STAR. Testing this hypothesis revealed that cAMP-induced STAR expression and steroidogenesis closely followed AKAP121 abundance when this AKAP was silenced or overexpressed in MA-10 cells, but that these changes were effected post-transcriptionally. Moreover, silencing AKAP121 expression in these cells specifically altered the localization of type II PKA regulatory subunit alpha (PKAR2A) at the mitochondria but did not affect its relative expression within the cell. Affinity purification experiments showed that PKAR2A preferentially associated with AKAP121, and cAMP analogs that activate type II PKA more efficiently induced STAR phosphorylation than analogs stimulating type I PKA. This suggests that AKAP121 and PKAR2A serve to enhance steroidogenesis by directing the synthesis and activation of STAR at the mitochondria in response to cAMP.

Key words: Cyclic adenosine monophosphate • Leydig cells • Signal transduction • Steroid hormones • A kinase anchoring proteins

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