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Curr Biol 2008 Oct 28;1820:1612-8. doi: 10.1016/j.cub.2008.09.024.
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Ca(2+) signaling occurs via second messenger release from intraorganelle synthesis sites.

Davis LC , Morgan AJ , Ruas M , Wong JL , Graeff RM , Poustka AJ , Lee HC , Wessel GM , Parrington J , Galione A .

Cyclic ADP-ribose is an important Ca(2+)-mobilizing cytosolic messenger synthesized from beta-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 ARCbeta and ARCgamma 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 beta-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 Ca(2+) 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.

PubMed ID: 18951023
PMC ID: PMC2581485
Article link: Curr Biol
Grant support: [+]

Genes referenced: arc1 bst1 LOC100887844 LOC115923516 LOC593358 LOC594349
Antibodies: arc1 Ab1 arc3 Ab1 bst1 Ab1

Article Images: [+] show captions
References [+] :
Bacher, Channelling of substrate promiscuity of the skeletal-muscle ADP-ribosyl cyclase isoform. 2004, Pubmed