A computational analysis of non-genomic plasma membrane progestin binding proteins: Signaling through ion channel-linked cell surface receptors

A number of plasma membrane progestin receptors linked to non-genomic events have been identified. These include: (1) α1-subunit of the Na⁺/K⁺-ATPase (ATP1A1), (2) progestin binding PAQR proteins, (3) membrane progestin receptor alpha (mPRα), (4) progesterone receptor MAPR proteins and (5) the association of nuclear receptor (PRB) with the plasma membrane. This study compares: the pore-lining regions (ion channels), transmembrane (TM) helices, caveolin binding (CB) motifs and leucine-rich repeats (LRRs) of putative progesterone receptors. ATP1A1 contains 10 TM helices (TM-2, 4, 5, 6 and 8 are pores) and 4 CB motifs; whereas PAQR5, PAQR6, PAQR7, PAQRB8 and fish mPRα each contain 8 TM helices (TM-3 is a pore) and 2–4 CB motifs. MAPR proteins contain a single TM helix but lack pore-lining regions and CB motifs. PRB contains one or more TM helices in the steroid binding region, one of which is a pore. ATP1A1, PAQR5/7/8, mPRα, and MAPR-1 contain highly conserved leucine-rich repeats (LRR, common to plant membrane proteins) that are ligand binding sites for ouabain-like steroids associated with LRR kinases. LRR domains are within or overlap TM helices predicted to be ion channels (pore-lining regions), with the variable LRR sequence either at the C-terminus (PAQR and MAPR-1) or within an external loop (ATP1A1). Since ouabain-like steroids are produced by animal cells, our findings suggest that ATP1A1, PAQR5/7/8 and mPRα represent ion channel-linked receptors that respond physiologically to ouabain-like steroids (not progestin) similar to those known to regulate developmental and defense-related processes in plants.