Cyclic ADP-ribose, frequently abbreviated as cADPR, is a cyclic adenine nucleotide (like
cAMP) with two phosphate groups present on 5' OH of the
adenosine (like
ADP), further connected to another
ribose at the 5' position, which, in turn, closes the cycle by
glycosidic bonding to the nitrogen 1 (N1) of the same
adenine base (whose position N9 has the glycosidic bond to the other
ribose).[1][2] The N1-glycosidic bond to adenine is what distinguishes cADPR from
ADP-ribose (ADPR), the non-cyclic analog. cADPR is produced from
nicotinamide adenine dinucleotide (NAD+) by ADP-ribosyl cyclases (
EC 3.2.2.5) as part of a
second messenger system.
Function
cADPR is a cellular messenger for
calcium signaling.[3] It stimulates calcium-induced calcium release at lower cytosolic concentrations of Ca2+. The primary target of cADPR is the
endoplasmic reticulum Ca2+ uptake mechanism. cADPR mobilizes Ca2+ from the endoplasmic reticulum by activation of
ryanodine receptors,[4] a critical step in muscle contraction.[5]
cADPR also acts as an
agonist for the
TRPM2 channel, but less potently than
ADPR.[6] cADPR and ADPR act
synergistically, with both molecules enhancing the action of the other molecule in activating the TRPM2 channel.[7]
Potentiation of Ca2+ release by cADPR is mediated by increased accumulation of Ca2+ in the
sarcoplasmic reticulum.[8]
Metabolism
cADPR and ADPR are synthesized from NAD+ by the bifunctional ectoenzymes of the
CD38 family (also includes the
GPI-anchored
CD157 and the specific, monofunctional ADP ribosyl cyclase of the mollusc Aplysia).[9][10][11] The same enzymes are also capable of hydrolyzing cADPR to
ADPR. Catalysis proceeds via a covalently bound intermediate. The hydrolysis reaction is inhibited by
ATP, and cADPR may accumulate. Synthesis and degradation of cADPR by enzymes of the CD38 family involve, respectively, the formation and the hydrolysis of the N1-glycosidic bond. In 2009, the first enzyme able to hydrolyze the phosphoanhydride linkage of cADPR, i.e. the one between the two phosphate groups, was reported.[12]
SARM1 and other
TIR domain-containing proteins also catalyze the formation of cADPR from NAD+.[13][14]
Isomers
Variants of cADPR that differ in their
HPLC retention times compared to canonical cADPR have been identified as products of bacterial and plant
TIR domain-containing enzymes.[14][15] v-cADPR (also referred to as 2'cADPR or 1''-2' glycocyclic ADPR (gcADPR)) and v2-cADPR (also referred to as 3'cADPR or 1''-3' gcADPR) isomers are cyclized by O-glycosidic bond formation between the ribose moieties in ADPR.[16][17] 3'cADPR produced by bacterial
TIR domain-containing proteins can act as an activator of bacterial antiphage defense systems and as a suppressor of plant immunity.[16]
^Santulli G, Marks AR (2015). "Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging". Current Molecular Pharmacology. 8 (2): 206–22.
doi:
10.2174/1874467208666150507105105.
PMID25966694.
^Canales J, Fernández A, Rodrigues JR, Ferreira R, Ribeiro JM, Cabezas A, Costas MJ, Cameselle JC (2009). "Hydrolysis of the phosphoanhydride linkage of cyclic ADP-ribose by the Mn2+-dependent ADP-ribose/CDP-alcohol pyrophosphatase". FEBS Lett. 583 (10): 1593–8.
doi:
10.1016/j.febslet.2009.04.023.
hdl:10400.8/3028.
PMID19379742.
S2CID28571921.