Getting specialized: presynaptic and postsynaptic dopamine D2 receptors

Abstract

Dopamine (DA) signaling controls many physiological functions ranging from locomotion to hormone secretion, and plays a critical role in addiction. DA elevation, for instance in response to drugs of abuse, simultaneously activates neurons expressing different DA receptors; how responses from diverse neurons/receptors are orchestrated in the generation of behavioral and cellular outcomes, is still not completely defined. Signaling from D2 receptors (D2Rs) is a good example to illustrate this complexity. D2Rs have presynaptic and postsynaptic localization and functions, which are shared by two isoforms in vivo. Recent results from knockout mice are clarifying the role of site and D2 isoform-specific effects thereby increasing our understanding of how DA modulates neuronal physiology.

Figure 1

Pre- and postsynaptic signaling mediated by D2L and D2S Schematic representation of D2R-mediated presynaptic and postsynaptic signaling in neurons. At the presynaptic site, D2Rs regulate synthesis and release of dopamine. D2S is the isoform involved in such function as reduced phosphorylation of TH is observed in D2R−/−, but not in D2L−/− mice. Presynaptically, D2Rs also modulate DAT activity, very likely through D2S, through a direct protein-protein interaction. At the postsynaptic site, D2L mediates G-proteins dependent and independent signaling. The figure shows a simplified scheme of D2R-mediated effects on the PKA and AKT pathways. Activation of D2Rs through the inhibition of adenylyl cyclase decreases DARPP-32 phosphorylation at Thr34. In addition, D2Rs stimulate Ca²⁺-dependent PP-2B activity further increasing dephosphorylation of DARPP-32 at Thr34. Both pathways contribute to a loss of inhibition of the phosphatase activity of PP-1. This signaling is lost in D2R−/− and in D2L−/− mice, pointing to D2L as the D2R isoform involved in postsynaptic signaling. Activation of D2Rs promotes the formation of a macromolecular complex composed of AKT/PP2-A/β-arrestin 2. Formation of this complex leads to the inactivation of AKT by PP2-A through dephosphorylation of Thr 308. Inactivation of AKT in response to DA results in the inactivation of GSK3, contributing to the expression of DA-associated behaviors.

Figure 2

Cellular effects of cocaine on striatal neurons. Upper panel: Simplified scheme of the effects of acute cocaine treatment in the striatum. Blockade of DAT by administration of cocaine stimulates DA release, which induces c-fos expression thorough a glutamate- and D1R-mediated mechanism. D2Rs are also stimulated upon cocaine treatment both pre- and postsynaptically. Presynaptically D2Rs modulate DA release, and postsynaptically they inhibit signaling from MSNs, and regulate glutamate, GABA and ACh release from cortical and striatal neurons. Lower panel : Administration of cocaine to D2R−/− mice leads to an impressive elevation of extracellular DA in the striatum, due to the loss of D2S-mediated autoreceptor’s function. However, despite an increased activation of D1Rs in D2R−/− mice, c-fos induction is dramatically suppressed. We hypothesize that this is due to loss of regulation of GABA and/or ACh release from striatal neurons and interneurons. ⊥ inhibition; ↓ activation; DA: dopamine/dopaminergic neuron; GABA: gamma-aminobutyric acid/GABAergic Interneuron ; ACh :Acetylcholine/Colinergic Interneuron; Glu: Glutamate/Glutamatergic neuron; DAT : dopamine transporter; D1: dopamine D1 receptor; D2: dopamine D2 receptor ; MSN: medium sized spiny neuron; VTA: ventral tegmental area; COC: cocaine.