Membrane coordination of receptors and channels mediating the inhibition of neuronal ion currents by ADP

Abstract

ADP and other nucleotides control ion currents in the nervous system via various P2Y receptors. In this respect, Cav2 and Kv7 channels have been investigated most frequently. The fine tuning of neuronal ion channel gating via G protein coupled receptors frequently relies on the formation of higher order protein complexes that are organized by scaffolding proteins and harbor receptors and channels together with interposed signaling components. However, ion channel complexes containing P2Y receptors have not been described. Therefore, the regulation of Cav2.2 and Kv7.2/7.3 channels via P2Y1 and P2Y12 receptors and the coordination of these ion channels and receptors in the plasma membranes of tsA 201 cells have been investigated here. ADP inhibited currents through Cav2.2 channels via both P2Y1 and P2Y12 receptors with phospholipase C and pertussis toxin-sensitive G proteins being involved, respectively. The nucleotide controlled the gating of Kv7 channels only via P2Y1 and phospholipase C. In fluorescence energy transfer assays using conventional as well as total internal reflection (TIRF) microscopy, both P2Y1 and P2Y12 receptors were found juxtaposed to Cav2.2 channels, but only P2Y1, and not P2Y12, was in close proximity to Kv7 channels. Using fluorescence recovery after photobleaching in TIRF microscopy, evidence for a physical interaction was obtained for the pair P2Y12/Cav2.2, but not for any other receptor/channel combination. These results reveal a membrane juxtaposition of P2Y receptors and ion channels in parallel with the control of neuronal ion currents by ADP. This juxtaposition may even result in apparent physical interactions between receptors and channels.

Ticagrelor Can Regulate the Ion Channel Characteristics of Superior Cervical Ganglion Neurons after Myocardial Infarction

“…In addition, many literature reports have shown that P2Y receptor affects the characteristics of neuronal ion channels and the release of neurotransmitters [ 32 , 35 , 36 , 37 ]. Similarly, P2Y12 also has a direct impact on ion channels [ 13 , 14 ], which may be involved in the regulation of SCG neuronal ion channel characteristics after MI.…”

“…After MI, the expression of P2Y12 receptors in some sympathetic ganglia increased significantly [ 11 ]. Moreover, P2Y12 affects ion channel characteristics [ 13 , 14 ]. P2Y12 receptor inhibitors can improve ion channel function [ 15 ] and protect against ischemia-induced neural injury [ 16 ].…”

A Role for The P2Y1 Receptor in Nonsynaptic Cross-depolarization in the Rat Dorsal Root Ganglia

“…The role of P2RY1 in CD reported here is consistent with previous reports. CD involves decreased membrane conductance (Amir and Devor 1996) and P2RY1 can trigger excitation of DRG neurons via an inhibition of Kv7 potassium channels (Yousuf, Klinger et al 2011, King and Scherer 2012, Gafar, Rodriguez et al 2016). This downstream mechanism may at least partly explain the regulatory role of P2RY1 in CD.…”

Human Peritoneal Mesothelial Cell Death Induced by High-Glucose Hypertonic Solution Involves Ca2+ and Na+ Ions and Oxidative Stress with the Participation of PKC/NOX2 and PI3K/Akt Pathways

“…Considering this, it is possible that the Na + influx mediated by SGLT due to the increased glucose gradient generates HPMC membrane depolarization with the subsequent activation of sodium and calcium channels. Alternatively, the glucose influx through SGLT or GLUT proteins could shift the ATP/ADP equilibrium promoting the activation of nucleotide-dependent sodium and calcium channels (Gafar et al, 2016 ). Further experiments must be performed using SGLT and/or GLUT inhibitors to evaluate these considerations.…”