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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 36

Module 2: Figure cADPR/NAADP function

Ca 2+ Ca 2+ AGONISTS
VOC TRPM2

Ca 2+ Cellular Ca 2+
metabolism +
Ca 2+
+
ATP
RYR NADH ADPR ?
NAD
NADP
+ +
+ Ca 2+ H S
ADP ribosyl cyclase
SERCA
Ca 2+ + cADPR

TPC1/2 + NAADP
Phosphatase
Ca 2+
Lysosome-related
+ NAAD
+ H organelle
H
Synthesis and mode of action of cADPR and NAADP.
The enzyme ADP-ribosyl cyclase is a bifunctional enzyme that has a synthase (S) component that synthesizes cADPR and NAADP from the precursors
NAD + and NADP respectively, but it also has a hydrolase (H) activity that converts cADPR into ADPR. This hydrolase is sensitive to metabolism
because it is inhibited by either ATP or NADH. The cADPR may act by stimulating the sarco/endo-plasmic reticulum Ca 2 + -ATPase (SERCA) pump to
increase the uptake of Ca 2 + into the endoplasmic reticulum. NAADP acts on a channel to release Ca 2 + from a lysosome-related organelle.

activated is still unclear. One suggestion is that the forma- cADPR control of Ca 2 + release
tion of cADPR and NAADP is sensitive to cellular meta- One of the major uncertainties about cADPR is its mode of
bolism (Module 2: Figure cADPR/NAADP function). In action in controlling the release of Ca 2 + . There have been
other words, cADPR and NAADP might be metabolic suggestions that it is a Ca 2 + -mobilizing second messenger
messengers that are capable of relaying information about that acts by stimulating the ryanodine receptors (RYRs) to
the state of cellular metabolism to the Ca 2 + signalling release Ca 2 + . However, direct evidence for this assertion is
pathways. Such a notion is supported by the fact that not particularly convincing. Early single channel record-
cADPR metabolism by the hydrolase is inhibited by either ings seemed to provide such evidence by showing that
ATP or NADH. Another suggestion is that it might be cADPR could open RYRs in lipid membranes, but these
activated by agonists acting through cell-surface recept- observations were challenged on the basis that the cADPR
ors, but the coupling mechanism remains to be established was acting through the ATP-binding site. When cADPR is
(Module 2: Figure cADPR/NAADP function). This ab- injected into cells, it usually fails to release Ca 2 + , but after a
sence of a coupling mechanism might be explained by the period of time, it can begin to enhance the sensitivity of the
cADPR working hypothesis if the external agonist en- RYRs. An example of such an effect is shown in heart cells,
hanced cADPR formation indirectly by first increasing where there is a gradual increase in spark frequency fol-
cellular metabolism. Such a mechanism could explain the lowing addition of cADPR (Module 2: Figure cADPR ac-
ability of β-adrenergic agents to increase cADPR levels in tion in heart cells). This observation on cardiac cells forms
heart. Likewise, the glucose-dependent increase in cADPR the basis of the second part of the cADPR working hypo-
in β-cells can be directly linked to the metabolism of gluc- thesis, which argues that cADPR acts indirectly as a modu-
ose, with the resulting increase in ATP acting to reduce lator of Ca 2 + release (Module 2: Figure cADPR/NAADP
the hydrolase activity (Module 2: Figure cADPR/NAADP function) by stimulating the sarco/endo-plasmic retic-
function). ulum Ca 2 + -ATPase (SERCA) pump to increase the load
In CD38 − / − mice, there is a decrease in the amount of Ca 2 + within the lumen of the store. This increase
of oxytocin (OT) released from hypothalamic neurons. in luminal Ca 2 + then sensitizes the RYRs so that they
Such mice show defects in maternal nurturing and in social either begin to open spontaneously to give Ca 2 + sparks
behaviour. (Module 2: Figure cADPR action in heart cells)orbegin to

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