Abstract

Inositol 1,4,5-trisphosphate (IP₃) and cyclic adenosine diphosphate-ribose (cADPR) are second messengers that enhance neurosecretion by inducing Ca²⁺ release 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 that NAADP causes a concentration-dependent increase in quantal output that is associated with an increase in probability of transmitter release at the frog neuromuscular junction. This effect is mimicked by A23187, a Ca ionophore that promotes Ca²⁺ entry at the plasmalemma. The response to NAADP is potentiated 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 the brain, enhances neurosecretion by releasing Ca²⁺ from an internal store near the plasmalemma, possibly from synaptic vesicles in the releasable pool. These data also support the hypothesis of a two-pool model for Ca²⁺oscillations at the presynaptic site.