CADP-ribose

Jun G et al. Ethnic differences in poly CADP-ribose) polymerase pseudogene genotype distribution association with lung cancer risk. Carcinogenesis 1999 20 1465-1469. 

Brading No one has mentioned yet that RyR function might be modified by other molecules such as the cADP ribose receptor. 

Li PL, Tang WX, Valdivia HH, Zou AP, Campbell WB 2001 cADP-ribose activates reconstitutes ryanodine receptors from coronary arterial smooth muscle. Am J Physiol... 

Kotlikoff That s a good question. It s a complicated situation. One knockout affects both the synthesis and the removal of cADP ribose. To my knowledge we don t have good probes that would allow us to selectively alter this in a way that we could make predictions and test them. 

Bradley Lukyanenko et al (2001) have published a paper in which they suggest that cADP ribose causes its effect by increasing SERCA activity, and the reason that cADP ribose releases Ca2+ from the stores is because the store Ca2+ content significantly increases. When you knock out FKBP12.6, do you get a significant reduction in your store content Could it be that cADP ribose isn t actually working on FKBP12.6, but instead on SERCA ... 

Lukyanenko V, Gyorke I, Wiesner TF, Gyorke S 2001 Potentiation of Ca2+ release by cADP ribose in the heart is mediated by enhanced SR Ca2+ uptake into the sarcoplasmic reticulum. Circ Res 89 614-622... 

The main mechanisms that are important are (1) SERCA pumps (2) phospholamban (3) Ca2+ binding proteins (4) inositohl,4,5-trisphosphate (L1SP3) receptors and mechanisms involved in InsP3 production (5) ryanodine receptors and cADP ribose production and (6) the cytoskeleton. 

In some cell types (including cardiac muscle cells, pancreatic cells), another second messenger", the cyclic ADP-ribose (Fig. 6.8), is involved in opening the ryanodin receptors (Lee et al., 1994). The cADP-ribose is formed from NAD by an enzymatic pathway with the help of an ADP-ribosyl cyclase. 

Adebanjo OA, Shankar VS, Pazianas M, Simon BJ, Lai FA, Huang CL-H, Zaidi M. 1996. Extracellularly applied ruthenium red and cADP ribose elevate cytosolic Ca2+ in isolated rat osteoclasts. Am J Physiol 270 F469-F475. 

Retinoids in Transmembrane Signaling Neutrophils treated with physiological concentrations of all-tra s-retinoic acid show a dose-dependent increase in synthesis of superoxide. Inhibitor studies suggest that retinoic acid acts via an inositol trisphosphate cascade rather than calcium and protein kinase C (Koga et al., 1997). There is also evidence that all-rrans-retinoic acid leads to increased formation of cADP-ribose and nicotinic acid adenine dinucleotide phosphate as second messengers (Section 8.4.4 Dousa et al., 1996 Mehta and Cheema, 1999). 

The nicotinamide nucleotide coenzymes function as electron carriers in a wide variety of redox reactions. In addition, NAD is the precursor of adenine dinucleotide phosphate (ADP)-ribose for ADP-ribosylation and poly(ADP-ribosylation) of proteins and cADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP). They act as second messengers and stimulate increases in intracellular calcium concentrations. 

NAD glycohydrolase, which releases nicotinamide and ADP-ribose. As discussed in Section 8.4.4, this enzyme also catalyzes the synthesis of cADP-ribose and nicotinic acid ADR which have roles in intracellular signaling. 

NAD is the source of ADP-ribose for the modification of proteins by mono-ADP-ribosylation, catalyzed by ADP-ribosyltransferases (Section 8.4.2), and poly(ADP-ribosylation), catalyzed by poly(ADP-ribose) polymerase (Section 8.4.3). It is also the precursor of two second messengers that act to increase the intracellular concentration of calcium, cADP-ribose, and nicotinic acid adenine dinucleotide phosphate (Section 8.4.4). 

Cyclization of ADP-ribose arising from NAD to cADP-ribose. 

The intracellular NAD glycohydrolase is now known as ADP-ribose cyclase there is also a cell surface ectozyme, identical with the lymphocyte CD38 antigen. CD38 also occurs intracellularly, in endosomes. Both enzymes catalyze the formation of both cADP-ribose and NAADP, as well as the glycohydrolase reaction. The cyclase reaction predominates at neutral pH, and the nicotinamide/nicotinic acid exchange reaction at acid pH, suggesting that in cytosol the main product of the soluble enzyme is cADP-ribose. In endosomes,... 

The role of cADP-ribose and NAADP in regulating cytosolic calcium may provide an alternative explanation to the serotonin hypothesis for the psychiatric and neurological signs of the niacin deficiency disease pellagra (Section 8.5 Petersen and Cancela, 1999). 

AU-trans-retinoic acid (Section 2.2.S.2) stimulates the synthesis of cADP-ribose in kidney cells in culture, apparendy as a result of the induction of CD38 (Beers et al., 1995 Takahashi et al., 1995) in ovariectomized rats, estradiol induces cytosolic ADP-ribosyl cyclase in the uterus, but not in estrogen unresponsive tissues (Chini et al., 1997). If this induction of ADP-ribose cyclase by estrogens leads to significant depletion of nicotinamide nucleotides, it may provide an additional explanation for the 2 1 excess of females to males in the incidence of pellagra (Section 8.5). 

The other characteristic feature of pellagra is the development of a depressive psychosis, superficially similar to schizophrenia and the organic psychoses, but clinically distinguishable by the sudden lucid phases that alternate with the most florid psychiatric signs. The mental symptoms may be the result of tryptophan depletion, and hence a lower availability of tryptophan for synthesis of the neurotransmitter serotonin (5-hydroxytryptophan). But the role of cADP-ribose and NAADP in controlling calcium release in response to neurotransmitters (Section 8.4.4) and impaired energy-yielding metabolism in the central nervous system as a result of depletion of NAD (P) may also be important. 

Wilson HL and Galione A (1998) Differential regulation of nicotinic acid-adenine dinucleotide phosphate and cADP-ribose production by cAMP and cGMP. Biochemical Journal331, 837-43. 

It is eilso the precursor of two second messengers that act to increase the intracellular concentration of calcium, cADP-ribose, tmd nicotinic acid adenine dinucleotide phosphate (Section 8.4.4). 

---