Abstract
BackgroundADP-ribosyl cyclases are remarkable enzymes capable of catalyzing multiple reactions including the synthesis of the novel and potent intracellular calcium mobilizing messengers, cyclic ADP-ribose and NAADP. Not all ADP-ribosyl cyclases however have been characterized at the molecular level. Moreover, those that have are located predominately at the outer cell surface and thus away from their cytosolic substrates.Methodology/Principal FindingsHere we report the molecular cloning of a novel expanded family of ADP-ribosyl cyclases from the sea urchin, an extensively used model organism for the study of inositol trisphosphate-independent calcium mobilization. We provide evidence that one of the isoforms (SpARC1) is a soluble protein that is targeted exclusively to the endoplasmic reticulum lumen when heterologously expressed. Catalytic activity of the recombinant protein was readily demonstrable in crude cell homogenates, even under conditions where luminal continuity was maintained.Conclusions/SignificanceOur data reveal a new intracellular location for ADP-ribosyl cyclases and suggest that production of calcium mobilizing messengers may be compartmentalized.
Highlights
Changes in cytosolic Ca2+ are indispensable for normal cell function [1]
ADP-ribosyl cyclase activity was first described in the sea urchin egg twenty years ago [2] but molecular information regarding these enzymes in this major model system has not been forthcoming
SpARC1 and SpARC2 appear more similar to Aplysia californica ADP-ribosyl cyclase and mammalian CD157 than to
Summary
Changes in cytosolic Ca2+ are indispensable for normal cell function [1]. This is not surprising given the multiple molecular targets for this ion. Cyclic ADP-ribose regulates ryanodine receptors on the (sarco)endoplasmic reticulum to mediate Ca2+-induced Ca2+ release [5], whereas NAADP probably targets novel Ca2+ channels [6] located on newly described acidic Ca2+ stores [7], this notion is somewhat controversial [8]. Quite remarkably, both of these messenger molecules are synthesized in vitro by the same family of enzymes – the ADP-ribosyl cyclases [9]. Our data reveal a new intracellular location for ADP-ribosyl cyclases and suggest that production of calcium mobilizing messengers may be compartmentalized
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