Role of Kv1 Potassium Channels in Regulating Dopamine Release and Presynaptic D2 Receptor Function

Philippe Martel,Stephanie Fulton,Louis-Eric Trudeau,Damiana Leo,Maxime Bérard,Colin Combs

doi:10.1371/journal.pone.0020402

Abstract

Dopamine (DA) release in the CNS is critical for motor control and motivated behaviors. Dysfunction of its regulation is thought to be implicated in drug abuse and in diseases such as schizophrenia and Parkinson's. Although various potassium channels located in the somatodendritic compartment of DA neurons such as G-protein-gated inward rectifying potassium channels (GIRK) have been shown to regulate cell firing and DA release, little is presently known about the role of potassium channels localized in the axon terminals of these neurons. Here we used fast-scan cyclic voltammetry to study electrically-evoked DA release in rat dorsal striatal brain slices. We find that although G-protein-gated inward rectifying (GIRK) and ATP-gated (KATP) potassium channels play only a minor role, voltage-gated potassium channels of the Kv1 family play a major role in regulating DA release. The use of Kv subtype-selective blockers confirmed a role for Kv1.2, 1.3 and 1.6, but not Kv1.1, 3.1, 3.2, 3.4 and 4.2. Interestingly, Kv1 blockers also reduced the ability of quinpirole, a D2 receptor agonist, to inhibit evoked DA overflow, thus suggesting that Kv1 channels also regulate presynaptic D2 receptor function. Our work identifies Kv1 potassium channels as key regulators of DA release in the striatum.

Highlights

Dopamine (DA) release in the CNS is critical for motor control by basal ganglia circuits and a dysfunction of its regulation is thought to be implicated in adaptations of the brain in response to drugs of abuse as well as in diseases such as schizophrenia and Parkinson’s
Potassium channel regulation of DA release A number of potassium channels have been demonstrated to be present in the somatodendritic compartment of DA neurons
D2 receptors can activate potassium conductances in the somatodendritic compartment of DA neurons that are compatible with the properties of G-proteingated inward rectifying K+ channels (GIRKs) channels (Lacey et al 1987, Uchida et al 2000)

Summary

Introduction

Dopamine (DA) release in the CNS is critical for motor control by basal ganglia circuits and a dysfunction of its regulation is thought to be implicated in adaptations of the brain in response to drugs of abuse as well as in diseases such as schizophrenia and Parkinson’s. DA has long been known to regulate its own release through the activation of autoreceptors [1]. The activation of D2 autoreceptors located on the soma and dendrites of DA neurons inhibits cell firing [2,3,4] and decreases somatodendritic DA release [5,6,7]. It can activate DA reuptake [8,9] and inhibit DA synthesis [10,11,12,13]. A specific role for the D2-short splice variant of the D2 receptor in this process was confirmed by the near absence of autoreceptor function in D2 knockout mice [21,22,23,24], and the maintenance of D2-autoreceptor function in D2-long knockout mice [21] and in D3 knockout mice [25]

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Results

Conclusion