IP3 receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer

Contact sites of endoplasmic reticulum (ER) and mitochondria locally convey calcium signals between the IP3 receptors (IP3R) and the mitochondrial calcium uniporter, and are central to cell survival. It remains unclear whether IP3Rs also have a structural role in contact formation and whether the different IP3R isoforms have redundant functions. Using an IP3R-deficient cell model rescued with each of the three IP3R isoforms and an array of super-resolution and ultrastructural approaches we demonstrate that IP3Rs are required for maintaining ER-mitochondrial contacts. This role is independent of calcium fluxes. We also show that, while each isoform can support contacts, type 2 IP3R is the most effective in delivering calcium to the mitochondria. Thus, these studies reveal a non-canonical, structural role for the IP3Rs and direct attention towards the type 2 IP3R that was previously neglected in the context of ER-mitochondrial calcium signaling

Initial Results from the Nobeyama Molecular Gas Observations of Distant Bright Galaxies

We present initial results from the CO survey toward high redshift galaxies using the Nobeyama 45m telescope. Using the new wide bandwidth spectrometer equipped with a two-beam SIS receiver, we have robust new detections of three high redshift (z=1.6-3.4) submillimeter galaxies (SXDF 1100.001, SDP9, and SDP17), one tentative detection (SDSS J160705+533558), and one non-detection (COSMOS-AzTEC1). The galaxies observed during the commissioning phase are sources with known spectroscopic redshifts from previous optical or from wide-band submm spectroscopy. The derived molecular gas mass and line widths from Gaussian fits are ~10^11 Msun and 430-530 km/s, which are consistent with previous CO observations of distant submm galaxies and quasars. The spectrometer that allows a maximum of 32 GHz instantaneous bandwidth will provide new science capabilities at the Nobeyama 45m telescope, allowing us to determine redshifts of bright submm selected galaxies without any prior redshift information.Comment: 4 pages, 1 figure, PASJ Letter Accepte

C2 domains from different Ca\u3csup\u3e2+\u3c/sup\u3e signaling pathways display functional and mechanistic diversity

The ubiquitous C2 domain is a conserved Ca2+-triggered membrane-docking module that targets numerous signaling proteins to membrane surfaces where they regulate diverse processes critical for cell signaling. In this study, we quantitatively compared the equilibrium and kinetic parameters of C2 domains isolated from three functionally distinct signaling proteins: cytosolic phospholipase A2-α (cPLA2-α), protein kinase C-β (PKC-β), and synaptotagmin-IA (Syt-IA). The results show that equilibrium C2 domain docking to mixed phosphatidylcholine and phosphatidylserine membranes occurs at micromolar Ca2+ concentrations for the cPLA2-α C2 domain, but requires 3- and 10-fold higher Ca2+ concentrations for the PKC-β and Syt-IA C2 domains ([Ca2+]1/2 = 4.7, 16, 48 μM, respectively). The Ca2+-triggered membrane docking reaction proceeds in at least two steps: rapid Ca2+ binding followed by slow membrane association. The greater Ca2+ sensitivity of the cPLA2-α domain results from its higher intrinsic Ca2+ affinity in the first step compared to the other domains. Assembly and disassembly of the ternary complex in response to rapid Ca2+ addition and removal, respectively, require greater than 400 ms for the cPLA2-α domain, compared to 13 ms for the PKC-β domain and only 6 ms for the Syt-IA domain. Docking of the cPLA2-α domain to zwitterionic lipids is triggered by the binding of two Ca2+ ions and is stabilized via hydrophobic interactions, whereas docking of either the PKC-β or the Syt-IA domain to anionic lipids is triggered by at least three Ca2+ ions and is maintained by electrostatic interactions. Thus, despite their sequence and architectural similarity, C2 domains are functionally specialized modules exhibiting equilibrium and kinetic parameters optimized for distinct Ca2+ signaling applications. This specialization is provided by the carefully tuned structural and electrostatic parameters of their Ca2+- and membrane-binding loops, which yield distinct patterns of Ca2+ coordination and contrasting mechanisms of membrane docking