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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 37

Module 2: Figure cADPR action in heart cells

Effect of cADPR on spark frequency in heart cells.
When permeabilized rat ventricular myocytes were treated with 5 μM cADPR, there was a gradual increase in spark frequency that recovered to the
resting level when it was washed off (wo). There was no change in spark amplitude. This increase in spark frequency was shown to depend upon
sensitization of the RYRs due to an increase in the luminal load of Ca 2 + resulting from an increase in the activity of the sarco/endo-plasmic reticulum
Ca 2 + -ATPase (SERCA) pump. Reproduced from Lukyanenko, V., Gy¨ orke, I., Wiesner, T.F. and Gy¨ orke, S. (2001) Potentiation of Ca 2 + release by
cADP-ribose in the heart is mediated by enhanced SR Ca 2 + uptake into the sarcoplasmic reticulum. Circ. Res. 89:614--622, with permission from
Lippincott Williams & Wilkins (http://lww.com);see Lukyanenko et al. 2001.

produce larger Ca 2 + transients when activated by a pulse zyme synthesizes both messengers. The NAADP control
of trigger Ca 2 + as occurs in neurons (Module 2: Figure of Ca 2 + release depends upon this messenger acting on a
cADPR action in neurons). store that is different from that controlled by the inositol
1,4,5-trisphosphate receptors (InsP 3 Rs) or the ryanodine
cADPR and cell regulation receptors (RYRs). A relationship between NAADP and
A role for cADPR has been implicated in a number of cell regulation seems to depend upon its interaction with
different cell types:
the other Ca 2 + -mobilizing messenger systems.
• Insulin-secreting β-cells (Module 7: Figure β-cell sig-
nalling) NAADP generation and metabolism
• Hypothalamic neurons: in CD38 − / − mice, there is a NAADP (Module 2: Figure NAADP structure) is another
decrease in the amount of oxytocin (OT) released from member of the NAD signalling pathways. Its synthesis
hypothalamic neurons. Such mice show defects in ma- from NADP is closely linked to that of cADPR in that
ternal nurturing and in social behaviour. they both share the same enzyme: the ADP-ribosyl cyc-
lase (Module 2: Figure cADPR/NAADP function). This
Nicotinic acid--adenine dinucleotide enzyme uses NAD + to make cADPR through a cycliza-
phosphate (NAADP) signalling tion reaction, or it can use NADP as a substrate to produce
NAADP is one of the messengers associated with the NAADP through a base-exchange reaction during which
NAD signalling pathways. NAADP has attracted consid- the nicotinamide group is exchanged for nicotinic acid.
erable attention as a Ca 2 + -mobilizing second messenger. Unlike cADPR, which is hydrolysed by the same en-
NAADP generation and metabolism is unusual in that it zyme, NAADP is degraded to NAAD by phosphatases
is closely allied to that of cADPR in that the same en- such as alkaline phosphatase.

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