Ca2+ Signaling Occurs via Second Messenger Release from Intraorganelle Synthesis Sites

Lianne C. Davis, Anthony J. Morgan, Margarida Ruas, Julian L. Wong, Richard M. Graeff, Albert J. Poustka, Hon Cheung Lee, Gary M. Wessel, John Parrington, Antony Galione

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Cyclic ADP-ribose is an important Ca2+-mobilizing cytosolic messenger synthesized from β-NAD+ by ADP-ribosyl cyclases (ARCs). However, the focus upon ectocellular mammalian ARCs (CD38 and CD157) has led to confusion as to how extracellular enzymes generate intracellular messengers in response to stimuli. We have cloned and characterized three ARCs in the sea urchin egg and found that endogenous ARCβ and ARCγ are intracellular and located within the lumen of acidic, exocytotic vesicles, where they are optimally active. Intraorganelle ARCs are shielded from cytosolic substrate and targets by the organelle membrane, but this barrier is circumvented by nucleotide transport. We show that a β-NAD+ transporter provides ARC substrate that is converted luminally to cADPR, which, in turn, is shuttled out to the cytosol via a separate cADPR transporter. Moreover, nucleotide transport is integral to ARC activity physiologically because three transport inhibitors all inhibited the fertilization-induced Ca2+ wave that is dependent upon cADPR. This represents a novel signaling mechanism whereby an extracellular stimulus increases the concentration of a second messenger by promoting messenger transport from intraorganelle synthesis sites to the cytosol.

Original languageEnglish (US)
Pages (from-to)1612-1618
Number of pages7
JournalCurrent Biology
Volume18
Issue number20
DOIs
StatePublished - Oct 28 2008
Externally publishedYes

Bibliographical note

Funding Information:
This research was supported by NIMH Grant R01 MH39936-04 (Dr. Folstein) and The John Merck Fund (Dr. Piven). The authors acknowledge the help of Pat Palmer, Ph.D., Stephan Arndt, Ph.D., and Janiece Thein.

Keywords

  • SIGNALING

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