Second messenger function and the structure-activity relationship of cyclic adenosine diphosphoribose (cADPR)

Area of Science:

• Cellular Biology
• Biochemistry
• Molecular Signaling

Background:

• Cyclic ADP-ribose (cADPR) acts as a crucial second messenger, regulating calcium (Ca2+) mobilization across diverse cell types, tissues, and organisms.
• The formation of cADPR involves either ectoenzyme CD38-mediated processes with NAD shuttling or intracellular ADP-ribosyl cyclases.
• cADPR influences cellular calcium dynamics by activating intracellular Ca2+ release and Ca2+ entry.

Purpose of the Study:

• To elucidate the precise molecular mechanisms by which cADPR modulates intracellular calcium levels.
• To investigate the potential binding interactions of cADPR with ryanodine receptors or associated proteins.
• To explore the structure-activity relationships of cADPR through the development of novel analogues.

Main Methods:

• Utilized novel cADPR analogues for structure-activity relationship studies.
• Investigated cADPR's role in calcium release via ryanodine receptors (types 2 and 3).
• Examined cADPR-mediated calcium entry, potentially involving capacitative calcium entry and the TRPM2 channel.

Main Results:

• Development of simplified cADPR analogues retaining significant biological activity through ribose substitutions.
• Confirmed cADPR's activation of intracellular Ca2+ release through ryanodine receptors.
• Demonstrated cADPR's capacity to evoke Ca2+ entry, possibly via capacitative Ca2+ entry or TRPM2 channel activation.

Conclusions:

• Novel cADPR analogues provide valuable tools for understanding cADPR's structure-activity dynamics.
• The precise mechanism of cADPR action on ryanodine receptors requires further elucidation.
• cADPR plays a multifaceted role in calcium signaling, impacting both Ca2+ release and entry pathways.