Interaction of luminal calcium and cytosolic ATP in the control of type 1 inositol (1,4,5)-trisphosphate receptor channels

Abstract

Ca2+ within intracellular stores (luminal Ca2+) is believed to play a role in regulating Ca2+ release into the cytosol via the inositol (1,4,5)-trisphosphate (Ins(1,4,5)-P3)-gated Ca2+ channel (or Ins(1,4,5)P3 receptor). To investigate this, we incorporated purified Type 1 Ins(1,4,5)-P3 receptor from rat cerebellum into planar lipid bilayers and monitored effects at altered luminal [Ca2+] using K+ as the current carrier. At a high luminal [Ca2+] and in the presence of optimal [Ins(1,4,5)P3] and cytosolic [Ca2+], a short burst of Ins(1,4,5)P3 receptor channel activity was followed by complete inactivation. Lowering the luminal [Ca2+] caused the channel to reactivate indefinitely. At luminal [Ca2+], reflecting a partially empty store, channel activity did not inactivate. The addition of cytosolic ATP to a channel inactivated by high luminal [Ca2+] caused reactivation. We provide evidence that luminal Ca2+ is exerting its effects via a direct interaction with the luminal face of the receptor. Activation of the receptor by ATP may act as a device by which cytosolic Ca2+ overload is prevented when the energy state of the cell is compromised.