Presynaptic Dopamine D2 Receptors Modulate [H-3] GABA Release at StriatoPallidal Terminals via Activation of PLC - IP3 - Calcineurin and Inhibition of AC - cAMP - PKA Signaling Cascades

摘要

Striatal dopamine D2 receptors activate the PLC - IP3 - Calcineurin-signaling pathway to modulate the neural excitability of En+ Medium-sized Spiny GABAergic neurons (MSN) through the regulation of L-type Ca2+ channels. Presynaptic dopaminergic D2 receptors modulate GABA release at striatopallidal terminals through L-type Ca2+ channels as well, but their signaling pathway is still undetermined. Since D2 receptors are Gi/o-coupled and negatively modulate adenylyl cyclase (AC), we investigated whether presynaptic D2 receptors modulate GABA release through the same signaling cascade that controls excitability in the striatum or by the inhibition of AC and decreased PKA activity. Activation of D2 receptors stimulated formation of [H-3] IP1 and decreased Forskolin-stimulated [H-3] cAMP accumulation in synaptosomes from rat Globus Pallidus. D2 receptor activation with Quinpirole in the presence of L 745,870 decreased, in a dose-dependent manner, K+-induced [H-3] GABA release in pallidal slices. The effect was prevented by the pharmacological blockade of Gi/o beta gamma subunit effects with Gallein, PLC with U 73122, IP3 receptor activation with 4-APB, Calcineurin with FK506. In addition, when release was stimulated with Forskolin to activate AC, D2 receptors also decreased K+-induced [H-3] GABA release, an effect occluded with the effect of the blockade of PKA with H89 or stimulation of release with the cAMP analog 8-Br-cAMP. These data indicate that D2 receptors modulate [H-3] GABA release at striatopallidal terminals by activating the PLC - IP3 - Calcineurin-signaling cascade, the same one that modulates excitability in soma. Additionally, D2 receptors inhibit release when AC is active. Both mechanisms appear to converge to regulate the activity of presynaptic L-type Ca2+ channels. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.