Journal articles

Background: Inositol 1,4,5-trisphosphate receptors (IP 3R) are expressed in almost all animal cells. Three mammalian genes encode closely related IP 3R subunits, which assemble into homo- or hetero-tetramers to form intracellular Ca 2 + channels. Scope of the review: In this brief review, we first consider a variety of complementary methods that allow the links between IP 3 binding and channel gating to be defined. How does IP 3 binding to the IP 3-binding core in each IP 3R subunit cause opening of a cation-selective pore formed by residues towards the C-terminal?

BACKGROUND: Inositol 1,4,5-trisphosphate receptors (IP3R) are expressed in almost all animal cells. Three mammalian genes encode closely related IP3R subunits, which assemble into homo- or hetero-tetramers to form intracellular Ca2+ channels. SCOPE OF THE REVIEW: In this brief review, we first consider a variety of complementary methods that allow the links between IP3 binding and channel gating to be defined. How does IP3 binding to the IP3-binding core in each IP3R subunit cause opening of a cation-selective pore formed by residues towards the C-terminal?

Quantification of the associations between biomolecules is required both to predict and understand the interactions that underpin all biological activity. Fluorescence polarization (FP) provides a nondisruptive means of measuring the association of a fluorescent ligand with a larger molecule. We describe an FP assay in which binding of fluorescein-labeled inositol 1,4,5-trisphosphate (IP(3)) to N-terminal fragments of IP(3) receptors can be characterized at different temperatures and in competition with other ligands.

Ca(2+) release by d-myo-inositol 1,4,5-trisphosphate receptors (IP(3)Rs) is widely considered to require the vicinal 4,5-bisphosphate motif of IP(3), with P-5 and P-4 engaging the alpha and beta domains of the binding site; using synthesis and mutagenesis we show that the adenine of synthetic glyconucleotides, through an interaction with Arg504, can replace the interaction of either P-1 or P-5 with the alpha-domain producing, respectively, the most potent bisphosphate agonist yet synthesised and the first agonist of IP(3)R without a vicinal bisphosphate motif; this will stimulate new approa

Inositol 1,4,5-trisphosphate (IP(3)) receptors (IP(3)R) are intracellular Ca(2+) channels. Their opening is initiated by binding of IP(3) to the IP(3)-binding core (IBC; residues 224-604 of IP(3)R1) and transmitted to the pore via the suppressor domain (SD; residues 1-223). The major conformational changes leading to IP(3)R activation occur within the N terminus (NT; residues 1-604).

All Ca(2+) channels are regulated by Ca(2+), a feature that allows them to respond to their own activity and to the activities of neighboring Ca(2+) channels. Inhibition by Ca(2+) protects cells from potentially hazardous increases in cytosolic [Ca(2+)], and stimulation can mediate facilitation and regenerative propagation of Ca(2+) signals. Calmodulin is emerging as a key player in regulation of Ca(2+) channels by Ca(2+), but its role is more complex and more beautiful than might have been imagined.

Malignant mesothelioma is an aggressive tumour of the pleura (MPM) or peritoneum with a clinical presentation at an advanced stage of the disease. Current therapies only marginally improve survival and there is an urgent need to identify new treatments. Carcinoma-associated fibroblasts (CAFs) represent the main component of a vast stroma within MPM and play an important role in the tumour microenvironment.