NAD+ surfaces again

Abstract

NAD + and its metabolites serve important functions in intracellular signalling. NAD + -mediated regulatory processes also take place on the cell surface, particularly of immune cells. In this issue of the Biochemical Journal, Gerth et al. have demonstrated a new mechanism of Ca 2+ uptake into monocytes which is triggered by NAD + or its degradation product, ADP-ribose. These observations point to a hitherto unknown Ca 2+ -influx mechanism and underscore the potential significance of NAD + and ADP-ribose as signalling molecules on the extracellular side of the plasma membrane.Key words: ADP-ribose, calcium, ion transport, immune cell, NAD + , pyridine nucleotide.From most textbooks of biochemistry one may still get the impression that the pyridine nucleotides have been invented just to make our lives a bit easier -they mediate the majority of redox reactions as cofactors (and there are few alternatives). Moreover, pyridine nucleotides contain an AMP moiety, which is also part of ATP. Therefore efforts to memorize the structures of NAD(P) can be limited to nicotinamide mononucleotide, the other half of these molecules. However, as a result of research over the past 15-20 years a far more complicated picture has emerged also placing NAD(P) + at key positions in cellular signal transduction [1]. Most remarkably, NAD(P) + undergoes structural conversions in these regulatory pathways, including the generation of new molecules [among them, cADPR (cyclic ADP-ribose), O-acetyl ADP-ribose and NAADP (nicotinic acid-adenine dinucleotide phosphate)]; compounds that are not known to participate in any other biochemical pathway.So far, most of the NAD + -dependent signalling processes have been shown to contribute to the control of intracellular events. For example, poly-ADP ribosylation takes place primarily in the nucleus and regulates DNA repair, transcription, apoptosis and other fundamental cellular processes. The NAD + -derivative cADPR activates Ca 2+ release from the endoplasmic reticulum and thereby Ca 2+ -dependent pathways. On the other hand, although also present within cells, mono-ADP-ribosylation appears to be largely an extracellular mechanism of NAD + -mediated regulation. All identified ARTs (mono-ADP-ribosyl transferases) of higher eukaryotes are either GPI (glycosylphosphatidylinositol)-anchored or secreted [2,3]. These enzymes transfer the ADPR (ADP-ribose) moiety of NAD + on to acceptor proteins, thereby modulating their biological activities. ARTs are apparently primarily expressed in blood cells and may contribute to immune functions by modifying proteins, for example, of the extracellular matrix [2,3]. Surprisingly, the known mammalian enzymes catalysing the synthesis of cADPR, designated ADP-ribosyl cyclases, are also located on the cell surface (again, primarily of blood cells). This is unexpected inasmuch as the generated messenger, cADPR, has an intracellular function. Despite appreciable efforts, so far no mammalian intracellular ADP-ribosyl cyclase has been characterized at the molecular level. S...

β-Nicotinamide adenine dinucleotide is an inhibitory neurotransmitter in visceral smooth muscle

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Changes in mitochondrial energy utilization in young and old worker honeybees (Apis mellifera)

“…A decrease in this action results in a decrease in ΔΨm and a subsequent decrease in NAD + concentration. Calorie restriction (CR), which can also extend the life span of organisms, is (Lin et al 2002;Qin et al 2006;Ziegler and Niere 2004). Thus, high NAD + levels may play a role in the trophocytes and fat cells of young workers similar to that in CR.…”

Emerging Functions of Extracellular Pyridine Nucleotides

“…CD38 plays a central role in these processes by regulating the concentrations of all of the nucleotide players. Adapted from (10).…”