Modulation of Ca2+-currents by sequential and simultaneous activation of adenosine A1 and A2A receptors in striatal projection neurons

摘要

D1- and D2-types of dopamine receptors are located separately in direct and indirect pathway striatal projection neurons (dSPNs and iSPNs). In comparison, adenosine A1-type receptors are located in both neuron classes, and adenosine A2A-type receptors show a preferential expression in iSPNs. Due to their importance for neuronal excitability, Ca²⁺-currents have been used as final effectors to see the function of signaling cascades associated with different G protein-coupled receptors. For example, among many other actions, D1-type receptors increase, while D2-type receptors decrease neuronal excitability by either enhancing or reducing, respectively, CaV1 Ca²⁺-currents. These actions occur separately in dSPNs and iSPNs. In the case of purinergic signaling, the actions of A1- and A2A-receptors have not been compared observing their actions on Ca²⁺-channels of SPNs as final effectors. Our hypotheses are that modulation of Ca²⁺-currents by A1-receptors occurs in both dSPNs and iSPNs. In contrast, iSPNs would exhibit modulation by both A1- and A2A-receptors. We demonstrate that A1-type receptors reduced Ca²⁺-currents in all SPNs tested. However, A2A-type receptors enhanced Ca²⁺-currents only in half tested neurons. Intriguingly, to observe the actions of A2A-type receptors, occupation of A1-type receptors had to occur first. However, A₁-receptors decreased Ca_V2 Ca²⁺-currents, while A_2A-type receptors enhanced current through Ca_V1 channels. Because these channels have opposing actions on cell discharge, these differences explain in part why iSPNs may be more excitable than dSPNs. It is demonstrated that intrinsic voltage-gated currents expressed in SPNs are effectors of purinergic signaling that therefore play a role in excitability.