Ca2+ release triggered by NAADP in hepatocyte microsomes

Area of Science:

• Cellular Biology
• Molecular Physiology
• Calcium Signaling

Background:

• Nicotinic acid-adenine dinucleotide phosphate (NAADP) is an emerging intracellular calcium (Ca2+)-mobilizing messenger.
• NAADP-mediated Ca2+ release operates through mechanisms distinct from inositol 1,4,5-trisphosphate (IP3) and cyclic ADP-ribose (cADPR).

Purpose of the Study:

• To investigate the characteristics of NAADP-induced Ca2+ release in rat hepatocyte microsomes.
• To compare the properties of NAADP-mediated Ca2+ release with those induced by IP3 and cADPR.

Main Methods:

• Micromolar concentrations of NAADP were used to trigger Ca2+ release from isolated rat hepatocyte microsomes.
• Experiments assessed cross-desensitization between NAADP, IP3, and cADPR.
• The effects of thapsigargin, pH, extracellular Ca2+, IP3 receptor inhibitors, ryanodine receptor inhibitors, verapamil, and diltiazem on NAADP-induced Ca2+ release were evaluated.

Main Results:

• NAADP triggered Ca2+ release from rat hepatocyte microsomes, independent of IP3 and cADPR cross-desensitization.
• Non-activating NAADP concentrations could inactivate the NAADP-sensitive Ca2+-release mechanism.
• NAADP-induced Ca2+ release was insensitive to extracellular Ca2+ concentration and pH (6.4-7.8), unlike IP3 and cADPR.
• Verapamil and diltiazem inhibited NAADP-induced Ca2+ release, but not that induced by IP3 or cADPR.

Conclusions:

• NAADP represents a distinct Ca2+ signaling pathway with unique regulatory properties.
• The NAADP-sensitive Ca2+ release mechanism in hepatocytes differs from those activated by IP3 and cADPR.
• Specific channel blockers like verapamil and diltiazem may target the NAADP-mediated Ca2+ release pathway.