Tài liệu Báo cáo khoa học: Second messenger function and the structure–activity relationship of

MINIREVIEW

Second messenger function and the structure–activity

relationship of cyclic adenosine diphosphoribose (cADPR)

Andreas H. Guse

University Medical Center Hamburg-Eppendorf, Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology I,

Cellular Signal Transduction, Hamburg, Germany

The cyclic ADP-ribose⁄Ca2+ signalling

pathway

Cyclic ADP-ribose (cADPR) was discovered in 1987 as

a Ca2+ mobilizing metabolite of the well-known co￾enzyme b-nicotinamide adenine dinucleotide (NAD) by

Lee and coworkers [1]. The cyclic structure of cADPR

was initially predicted to originate from an N-glycosyl

linkage between the anomeric carbon of the ribose,

which in the precursor NAD is linked to nicotinamide,

and the amino ⁄ imino group at C6 of the adenine

moiety [2]. Spectroscopic data [3] and finally a crystal

structure revealed cyclization between the anomeric

C1 of this ribose moiety (commonly termed ‘northern

ribose’ while the ribose linked to N9 of adenine is

called the ‘southern’ ribose; Fig. 1) and the N1 of the

adenine ring [4].

Besides d-myo-inositol 1,4,5-trisphosphate (InsP3)

and nicotinic acid adenine dinucleotide phosphate

(NAADP; reviewed in [4a]), cADPR is one of the prin￾cipal Ca2+-releasing second messengers involved in cel￾lular Ca2+ homeostasis. Changes in the cellular Ca2+

homeostasis are among the fundamental signalling pro￾cesses in multicellular organisms. Such changes occur

in response to extracellular signals, e.g. hormones,

mediators, cell–cell contacts or physical stimuli, and

represent one of the most important, powerful and ver￾satile intracellular signal transducers. Changes in the

Correspondence

A. H. Guse, University Medical Center

Hamburg-Eppendorf, Center of Experimental

Medicine, Institute of Biochemistry and

Molecular Biology I: Cellular Signal

Transduction, Martinistr. 52,

20246 Hamburg, Germany

Fax: +49 40 42803 9880

Tel: +49 40 42803 2828

E-mail: [email protected]

(Received 10 March 2005, accepted 05 July

2005)

doi:10.1111/j.1742-4658.2005.04863.x

Cyclic ADP-ribose (cADPR) is a Ca2+ mobilizing second messenger found

in various cell types, tissues and organisms. Receptor-mediated formation

of cADPR may proceed via transmembrane shuttling of the substrate

NAD and involvement of the ectoenzyme CD38, or via so far unidentified

ADP-ribosyl cyclases located within the cytosol or in internal membranes.

cADPR activates intracellular Ca2+ release via type 2 and 3 ryanodine

receptors. The exact molecular mechanism, however, remains to be elucida￾ted. Possibilities are the direct binding of cADPR to the ryanodine receptor

or binding via a separate cADPR binding protein. In addition to Ca2+

release, cADPR also evokes Ca2+ entry. The underlying mechanism(s) may

comprise activation of capacitative Ca2+ entry and ⁄ or activation of the

cation channel TRPM2 in conjunction with adenosine diphosphoribose.

The development of novel cADPR analogues revealed new insights into the

structure–activity relationship. Substitution of either the northern ribose or

both the northern and southern ribose resulted in much simpler molecules,

which still retained significant biological activity.

Abbreviations

ADPRC, ADP-ribosyl cyclase; 8-Br-N1-cIDPR, 8-bromo-cyclic inosine diphosphoribose; cADPcR, cyclic ADP carbocyclic ribose; cADPR, cyclic

adenosine diphosphoribose; cADPR-BP, cADPR binding protein; cArisDPR, cyclic aristeromycin diphosphoribose; N1-cIDPR, N1-coupled

cyclic inosine diphosphoribose; cIDP-DE, N1-[(phosphoryl-O-ethoxy)-methyl]-N9-[(phosphoryl-O-ethoxy)-methyl]-hypoxanthine-cyclic pyro￾phosphate; cIDPRE, N1-ethoxymethyl-cIDPR; CRAC, Ca2+ release activated Ca2+ channel; FKBP, FK506 binding protein; InsP3, D-myo-inositol

1,4,5-trisphosphate; NAADP, nicotinic acid adenine dinucleotide phosphate; RyR, ryanodine receptor; TRP, transient receptor potential.

4590 FEBS Journal 272 (2005) 4590–4597 ª 2005 FEBS