P2Y1 receptors mediate an activation of neuronal calcium-dependent K+ channels

摘要

Molecularly defined P2Y receptor subtypes are known to regulate the functions of neurons through an inhibition of KV7 K⁺ and CaV2 Ca²⁺ channels and via an activation or inhibition of Kir3 channels. Here, we searched for additional neuronal ion channels as targets for P2Y receptors. Rat P2Y1 receptors were expressed in PC12 cells via an inducible expression system, and the effects of nucleotides on membrane currents and intracellular Ca²⁺ were investigated. At a membrane potential of −30 mV, ADP induced transient outward currents in a concentration-dependent manner with half-maximal effects at 4 μm. These currents had reversal potentials close to the K⁺ equilibrium potential and changed direction when extracellular Na⁺ was largely replaced by K⁺, but remained unaltered when extracellular Cl⁻ was changed. Currents were abolished by P2Y1 antagonists and by blockade of phospholipase C. ADP also caused rises in intracellular Ca²⁺, and ADP-evoked currents were abolished when inositol trisphosphate-sensitive Ca²⁺ stores were depleted. Blockers of KCa2, but not those of KCa1.1 or KCa3.1, channels largely reduced ADP-evoked currents. In hippocampal neurons, ADP also triggered outward currents at −30 mV which were attenuated by P2Y1 antagonists, depletion of Ca²⁺ stores, or a blocker of KCa2 channels. These results demonstrate that activation of neuronal P2Y1 receptors may gate Ca²⁺-dependent K⁺ (KCa2) channels via phospholipase C-dependent increases in intracellular Ca²⁺ and thereby define an additional class of neuronal ion channels as novel effectors for P2Y receptors. This mechanism may form the basis for the control of synaptic plasticity via P2Y1 receptors.