Nicotinic acid adenine dinucleotide phosphate enhances quantal neurosecretion at the frog neuromuscular junction: Possible action on synaptic vesicles in the releasable pool

Inositol 1,4,5-trisphosphate (IP3) and cyclic adenosine diphosphate-ribose (cADPR) are second messengers that enhance neurosecretion by inducing Ca2release from smooth endoplasmic reticulum (SER). The putative intracellular messenger, nicotinic acid adenine dinucleotide phosphate (NAADP), releases Ca2+ from stores that are distinct from SER. Evidence is presented here th at NAADP causes a concentration-dependent increase in quantal output that i s associated with an increase in probability of transmitter release at the frog neuromuscular junction. This effect is mimicked by A23187, a Ca ionoph ore that promotes Ca2+ entry at the plasmalemma. The response to NAADP is p otentiated by IP3 but antagonized by cADPR. Thapsigargin completely blocks IP3 and cADPR responses and decreases but does not prevent the response to NAADP. We conclude that NAADP, whose receptors are widely distributed in th e brain, enhances neurosecretion by releasing Ca2+ from an internal store n ear the plasmalemma, possibly from synaptic vesicles in the releasable pool . These data also support the hypothesis of a two-pool model for Ca2+ oscil lations at the presynaptic site.