Abstract
Steroid hormones induce changes in gene expression by binding to intracellular receptors that then translocate to the nucleus. Steroids have also been shown to rapidly modify cell function by binding to surface membrane receptors. We identified a candidate steroid membrane receptor, the progestin and adipoQ receptor (PAQR) 10, a member of the PAQR family, in a screen for genes differentially expressed in mouse pancreatic beta-cells. PAQR10 gene expression was tissue restricted compared with other PAQRs. In the mouse embryonic pancreas, PAQR10 expression mirrored development of the endocrine lineage, with PAQR10 protein expression confined to endocrine islet-duct structures in the late embryo and neonate. In the adult mouse pancreas, PAQR10 was expressed exclusively in islet cells except for its reappearance in ducts of maternal islets during pregnancy. PAQR10 has a predicted molecular mass of 29 kDa, comprises seven transmembrane domains, and, like other PAQRs, is predicted to have an intracellular N-terminus and an extracellular C-terminus. In silico analysis indicated that three members of the PAQR family, PAQRs 9, 10, and 11, have a candidate mitochondrial localization signal (MLS) at the N-terminus. We showed that PAQR10 has a functional N-terminal MLS and that the native protein localizes to mitochondria. PAQR10 is structurally related to some bacterial hemolysins, pore-forming virulence factors that target mitochondria and regulate apoptosis. We propose that PAQR10 may act at the level of the mitochondrion to regulate pancreatic endocrine cell development/survival.
Highlights
Steroid hormones signal through intracellular receptors that translocate to the nucleus and function as transcriptional regulators of target genes
A BLAST search of the deduced BA12 protein sequence showed it to be identical to monocyte to macrophage differentiation 2 (Mmd2) factor, which had been identified in a screen for mouse gonad-specific genes [18], and to progestin adipoQ receptor 10 (PAQR 10) annotated in GenBank
We identified PAQR10, a member of the highly conserved progestin and adipoQ receptor (PAQR) gene family, in a screen for genes differentially expressed in pancreatic β-cell versus α-cell lines
Summary
Steroid hormones signal through intracellular receptors that translocate to the nucleus and function as transcriptional regulators of target genes. Other steroidinduced events are rapidly triggered independent of transcription via signaling pathways classically associated with cell membrane receptors, including ion channels, second messengers, and protein kinase cascades [1]. These so-called nongenomic effects of steroids include estrogen-induced proliferation of breast cancer cells [2], estrogen-induced vasodilation [3], and the progesterone-initiated acrosomal reaction in sperm [4]. The mechanisms underlying this rapid signaling by steroids are poorly defined. Studies have identified membrane-associated, steroid-binding proteins in different tissues and species, and there is evidence that some nongenomic steroid effects are mediated by classical G protein–coupled receptors (GPCRs) or involve cytoplasmic activation of the nuclear steroid receptors [reviewed in [5]].
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