If you are experiencing problems downloading PDF or HTML fulltext, our helpdesk recommend clearing your browser cache and trying again. If you need help in clearing your cache, please click here . Still need help? Email help@ingentaconnect.com

Free Content Subcellular and Intercellular Traffic of NAD+, NAD+ Precursors and NAD+-Derived Signal Metabolites and Second Messengers: Old and New Topological Paradoxes

 Download
(PDF 8,798.5kb)
 
Download Article:

Abstract:

NAD+ metabolism and regulation are still incompletely defined in their features. Specifically, several compartmentation problems, both subcellular and intercellular, have emerged in the past years. A topological paradox was identified in the CD38/NAD+/Cyclic ADP-ribose system which represents a means for achieving regulation of intracellular Calcium levels ([Ca2+]i and of Ca2+-mediated cell functions. CD38, an ectoenzyme featuring ADP-ribosyl cyclase (ADPRC) activity, is known to catalyze the generation of as many as eight Ca2+-active signal metabolites, including cADPR, ADPR, NAADP and three adenine homodinucleotides (Ap2A and two isomers thereof, designated P18 and P24). The first paradox concerns the ectocellular conversion of NAD+ to cADPR and the intracellular activity of cADPR as a potent Ca2+ mobilizer from stores expressing ryanodine receptors/channels on the endoplasmic/sarcoplasmic reticulum. This topological inconsistency was solved with the identification of hexameric Connexin 43 hemichannels (Cx43 HC) as an equilibrative transport system for NAD+, and of redundant equilibrative, and especially concentrative, transport systems for cADPR. Other transporters for NAADP+, P18 and P24 are still unknown. In addition, NAD+ itself and some of its derivatives were recognized to be agonists of purinergic receptors, e.g., P2Y11 and P2X7, thereby affecting the [Ca2+]i levels either through protein kinase A- and phospholipase C-mediated pathways or through direct influx of extracellular Ca2+, respectively. Finally, recent findings demonstrate that the enzymes involved in NAD+ biosynthesis and some of the enzymes involved in the multiple pathways of NAD+ utilization localize to distinct subcellular compartments of the same cell and, surprisingly, also to different cell types of the same organism. Therefore, NAD+ biosynthesis from several precursors, collectively defined Vitamin B3 forms, is at the same time an organismal and a cellular process, whose individual steps may occur in different cells/tissues/organs. Thus, a paracrine crosstalk is activated via the exchange of intermediate metabolites in biological fluids (e.g., Nicotinamide mononucleotide and Nicotinamide riboside), and the eventual NAD+ biosynthesis occurs in selected cells able to utilize it for the display of diverse, fundamental cell functions. These are driven by NAD+-consuming enzymes, as ADPRCs, mono ADP-ribosyltransferases, poly(ADP-ribose) polymerases and different sirtuins (NAD+-dependent protein deacetylases).

Keywords: CD38; CYCLIC ADP-RIBOSE; ECTOENZYMES; INTRACELLULAR CA2+; NAD+; NICOTINAMIDE MONONUCLEOTIDE

Document Type: Review Article

DOI: http://dx.doi.org/10.1166/msr.2012.1007

Publication date: June 1, 2012

More about this publication?
  • The MESSENGER is an international peer-reviewed journal, focused on all aspects of messenger-signaling. The MESSENGER is devoted to all aspects of messenger- signaling, from the upstream activation of the receptors of the first messengers to the downstream signaling cascades. Undoubtedly, more novel second messengers will be discovered, expanding the scope of the journal appropriately. The MESSENGER publishes review articles, full research articles and short communications of important new scientific findings on all research aspects of messengers.
  • Editorial Board
  • Information for Authors
  • Subscribe to this Title
  • ingentaconnect is not responsible for the content or availability of external websites
Related content

Tools

Favourites

Share Content

Access Key

Free Content
Free content
New Content
New content
Open Access Content
Open access content
Subscribed Content
Subscribed content
Free Trial Content
Free trial content
Cookie Policy
X
Cookie Policy
ingentaconnect website makes use of cookies so as to keep track of data that you have filled in. I am Happy with this Find out more