Circular RNA (circRNA) is a group of endogenous noncoding RNA characterized by a covalently closed cyclic structure lacking poly-adenylated tails. Recent studies have suggested that circRNAs play a crucial role in regulating gene expression by acting as a microRNA sponge, RNA binding protein sponge and translational regulator. CircRNAs have become a research hotspot because of their close association with the development of diseases. Some circRNAs are reportedly expressed in a tissue- and development stage-specific manner. Furthermore, due to other features of circRNAs including stability, conservation and high abundance in body fluids, circRNAs are believed to be potential biomarkers for various diseases. In the present review, we provide the current understanding of biogenesis and gene regulatory mechanisms of circRNAs, summarize the recent studies on circRNAs as potential diagnostic and prognostic biomarkers, and highlight the major advantages and limitations of circRNAs as novel biomarkers based on existing knowledge.
Rad/Rem/Gem/Kir (RGK) GTPases potently inhibit Ca V 1 and Ca V 2 (Ca V 1-2) channels, a paradigm of ion channel regulation by monomeric G-proteins with significant physiological ramifications and potential biotechnology applications. The mechanism(s) underlying how RGK proteins inhibit I Ca is unknown, and it is unclear how key structural and regulatory properties of these GTPases (such as the role of GTP binding to the nucleotide binding domain (NBD), and the C-terminus which contains a membrane-targeting motif) feature in this effect. Here, we show that Rem inhibits Ca V 1.2 channels by three independent mechanisms that rely on distinct configurations of the GTPase: (1) a reduction in surface density of channels is accomplished by enhancing dynamin-dependent endocytosis, (2)
Human bestrophin 1 (hBest1) is a calcium-activated chloride channel from the retinal pigment epithelium, where it can suffer mutations associated with vitelliform macular degeneration, or Best disease. We describe the structure of a bacterial homolog (KpBest) of hBest1 and functional characterizations of both channels. KpBest is a pentamer that forms a five-helix transmembrane pore, closed by three rings of conserved hydrophobic residues, and has a cytoplasmic cavern with a restricted exit. From electrophysiological analysis of structure-inspired mutations in KpBest and hBest1, we find a subtle control of ion selectivity in the bestrophins, including reversal of anion/cation selectivity, and dramatic activation by mutations at the exit restriction. A homology model of hBest1 shows the locations of disease-causing mutations and suggests possible roles in regulation.
Voltage-gated Ca2+ (Ca(V)) channels are central to the biology of excitable cells, and therefore regulating their activity has widespread applications. We describe genetically encoded molecules for inducibly inhibiting Ca(V) channels (GEMIICCs). GEMIICCs are derivatives of Rem, a Ras-like GTPase that constitutively inhibits Ca2+ currents (I(Ca)). C terminus-truncated Rem(1-265) lost the ability to inhibit I(Ca) owing to loss of membrane targeting. Fusing the C1 domain of protein kinase Cgamma to yellow fluorescent protein (YFP)-Rem(1-265) generated a molecule that rapidly translocated from cytosol to plasma membrane with phorbol-12,13-dibutyrate in human embryonic kidney cells. Recombinant Ca(V)2.2 and Ca(V)1.2 channels were inhibited concomitantly with C1(PKCgamma)-YFP-Rem(1-265) membrane translocation. The generality of the approach was confirmed by creating a GEMIICC using rapamycin-dependent heterodimerization of YFP-FKBP-Rem(1-265) and a constitutively membrane-targeted rapamycin-binding domain. GEMIICCs reduced I(Ca) without diminishing gating charge, thereby ruling out decreased number of surface channels and voltage-sensor immobilization as mechanisms for inhibition. We introduce small-molecule-regulated GEMIICCs as potent tools for rapidly manipulating Ca2+ signals in excitable cells.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.