NAADP is one of the most peculiar & powerful NAD metabolites: a calcium mobilizing 2nd messenger that is important for cell migration in response to IL8. For yrs, it was known to be produced by CD38 but how? We now know dx.doi.org/10.1096/fj.202…
It had been proposed that CD38 reacts on the outside of cells with nicotinic acid (NA) & NADP in an exchange reaction that would form the NAADP plus NAM but there are problems with this idea
1st, there isn't sufficient NA to do this rx. 2nd, forming NAADP outside of cells doesn't solve the problem of calcium mobilization from acidic intracellular stores. 3rd, there has to be a specific signal to form NAADP. NAADP is too powerful to be made willy nilly
Tae-Sik Nam, Dae-Ryoung Park, Uh-Hyun Kim & I figured out how & where NAADP is formed by CD38. It's truly amazing. Also, great thanks to So-Young Rah, Tae-Gyu Woo & Hun Taeg Chung in the Kim group at Chonbuk National University
IL8 starts a signaling cascade that assembles vacuolar ATPase on endolysosomes & stimulates EPAC-RAP1-PP2A-dependent dephosphorylation of Cx43. Cx43 is an NADP transporter that is active when dephosphorylated. CD38 is already on endolysosome membranes w active site in the lumen
Guess what else is in the lumen: the enzymes to make our old friend NAAD (NAPRT & NMNAT3). Really interesting because no one knew how NAD metabolites are made in organelles & NMNAT3 has been misclassified as a mito enzyme (mouse KO doesn't support mito localization)
So this means that there's NAAD being made in endolysosomes & that there are CD38 active sites in endolysosomes. IL8 leads to signal-dependent acidification & transport of NADP. Then CD38 exchanges the NAM piece of NADP off & uses the NA from NAAD to form NAADP. Astonishing!
If you are an NAD or calcium signaling person, you are experiencing maximal geeky pleasure. If you are a lay person, you may wonder, why is this interesting? This is, to my mind, the most tightly regulated set of NAD reactions that have ever been described
The discovery explains how cells convey calcium signals through the NAD system & have implications in development & metastasis. We don't usually know where basic research will lead
Back in the day, I was minding my own biz working on glutamine-dependent NAD synthetase when I realized that there might be another way to make NAD (the NR pathway). Watch for the Kim group & ours to make further discoveries on signal-dependent NAADP formation. Thanks for reading
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