Functional overlap of IP3- and cADP-ribose-sensitive calcium stores in guinea pig myenteric neurons

In myenteric neurons two different receptor subtypes govern the intracellul ar Ca2+ stores: the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) and the ryanodine receptor (RyR). Their degree of functional overlap was determ ined by examining Ca2+ release in these cells through both superfusion tech niques and intracellular microinjection. Microinjection of IP3 (50 muM) and cADP-ribose (cADPr, 50 muM), specific ligands for the IP3R and RyR, respec tively, demonstrated mobilization of intracellular Ca2+ stores. Perfusion w ith cinnarizine (50 muM) or dantrolene (10 muM), antagonists of the IP3R an d RyR, respectively, eliminated the Ca2+ response to microinjected IP3 and cADPr. Superfusion of the neurons with 100 muM ATP, an IP3-mediated Ca2+-mo bilizing agonist, caused intracellular Ca2+ increments, which were antagoni zed by cinnarizine, and the RyR antagonists dantrolene, procaine (5 mM), an d ryanodine (1 muM). Caffeine (10 mM) was applied repetitively in Ca2+-free conditions to deplete RyR-sensitive stores; subsequent perfusion with ATP demonstrated a Ca2+ response. Conversely, caffeine caused a Ca2+ response a fter repetitive ATP exposures. The internal Ca2+ stores of myenteric neuron s are governed by two receptor subtypes, IP3R and RyR, which share partial functional overlap.