cAMP-producing chemogenetic and adenosine A2a receptor activation inhibits the inwardly rectifying potassium current in striatal projection neurons

Qian Wang, Fuming Zhou

Research output: Contribution to journalArticle

Abstract

Adenosine A2a receptors (A2aRs) are highly and selectively expressed in D2-medium spiny neurons (D2-MSNs) that also express a high level of dopamine D2 receptors (D2Rs). However, it was not established how A2aR activity affects D2-MSN excitability, let alone the ion channels involved. We have performed two sets of experiments to determine the potential A2aR agonistic effects on D2-MSN intrinsic excitability and the underlying ion channel mechanism. First, we have used the cAMP-producing, G αs/olf coupled designer receptors exclusively activated by designer drug (Gs-DREADDs) to phenocopy cAMP-stimulating A2aR activation. We found that activation of Gs-DREADD inhibited the inwardly rectifying potassium current (Kir)–a key regulator of MSN excitability, caused a depolarization, increased input resistance, and substantially increased the intrinsic excitability of MSNs such that depolarizing inputs evoked many more action potentials. Second, we have determined that A2aR agonism produced these same excitatory effects on D2-MSN intrinsic excitability and spike firing, although at lower magnitudes than those induced by Gs-DREADD activation; furthermore, these A2aR-triggered excitatory effects were intact in the presence of a D2R antagonist. Taken together, these results clearly establish that in striatal D2-MSNs, A2aR activation can independently inhibit Kir and increase intrinsic excitability and spike and neurotransmitter output; our results also indicate that Gs-DREADD can serve as a broadly useful positive control for neurotransmitter receptors that increase intracellular cAMP levels and hence facilitate the determination of the cellular effects of these neurotransmitter receptors.

Original languageEnglish (US)
Pages (from-to)229-243
Number of pages15
JournalNeuropharmacology
Volume148
DOIs
StatePublished - Apr 1 2019

Fingerprint

Corpus Striatum
Neurotransmitter Receptor
Purinergic P1 Receptors
Ion Channels
Potassium
Designer Drugs
Neurons
Dopamine D2 Receptors
Action Potentials
Neurotransmitter Agents

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

@article{69a13e1e0f054e339c5fb02b216efe52,
title = "cAMP-producing chemogenetic and adenosine A2a receptor activation inhibits the inwardly rectifying potassium current in striatal projection neurons",
abstract = "Adenosine A2a receptors (A2aRs) are highly and selectively expressed in D2-medium spiny neurons (D2-MSNs) that also express a high level of dopamine D2 receptors (D2Rs). However, it was not established how A2aR activity affects D2-MSN excitability, let alone the ion channels involved. We have performed two sets of experiments to determine the potential A2aR agonistic effects on D2-MSN intrinsic excitability and the underlying ion channel mechanism. First, we have used the cAMP-producing, G αs/olf coupled designer receptors exclusively activated by designer drug (Gs-DREADDs) to phenocopy cAMP-stimulating A2aR activation. We found that activation of Gs-DREADD inhibited the inwardly rectifying potassium current (Kir)–a key regulator of MSN excitability, caused a depolarization, increased input resistance, and substantially increased the intrinsic excitability of MSNs such that depolarizing inputs evoked many more action potentials. Second, we have determined that A2aR agonism produced these same excitatory effects on D2-MSN intrinsic excitability and spike firing, although at lower magnitudes than those induced by Gs-DREADD activation; furthermore, these A2aR-triggered excitatory effects were intact in the presence of a D2R antagonist. Taken together, these results clearly establish that in striatal D2-MSNs, A2aR activation can independently inhibit Kir and increase intrinsic excitability and spike and neurotransmitter output; our results also indicate that Gs-DREADD can serve as a broadly useful positive control for neurotransmitter receptors that increase intracellular cAMP levels and hence facilitate the determination of the cellular effects of these neurotransmitter receptors.",
author = "Qian Wang and Fuming Zhou",
year = "2019",
month = "4",
day = "1",
doi = "10.1016/j.neuropharm.2019.01.014",
language = "English (US)",
volume = "148",
pages = "229--243",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - cAMP-producing chemogenetic and adenosine A2a receptor activation inhibits the inwardly rectifying potassium current in striatal projection neurons

AU - Wang, Qian

AU - Zhou, Fuming

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Adenosine A2a receptors (A2aRs) are highly and selectively expressed in D2-medium spiny neurons (D2-MSNs) that also express a high level of dopamine D2 receptors (D2Rs). However, it was not established how A2aR activity affects D2-MSN excitability, let alone the ion channels involved. We have performed two sets of experiments to determine the potential A2aR agonistic effects on D2-MSN intrinsic excitability and the underlying ion channel mechanism. First, we have used the cAMP-producing, G αs/olf coupled designer receptors exclusively activated by designer drug (Gs-DREADDs) to phenocopy cAMP-stimulating A2aR activation. We found that activation of Gs-DREADD inhibited the inwardly rectifying potassium current (Kir)–a key regulator of MSN excitability, caused a depolarization, increased input resistance, and substantially increased the intrinsic excitability of MSNs such that depolarizing inputs evoked many more action potentials. Second, we have determined that A2aR agonism produced these same excitatory effects on D2-MSN intrinsic excitability and spike firing, although at lower magnitudes than those induced by Gs-DREADD activation; furthermore, these A2aR-triggered excitatory effects were intact in the presence of a D2R antagonist. Taken together, these results clearly establish that in striatal D2-MSNs, A2aR activation can independently inhibit Kir and increase intrinsic excitability and spike and neurotransmitter output; our results also indicate that Gs-DREADD can serve as a broadly useful positive control for neurotransmitter receptors that increase intracellular cAMP levels and hence facilitate the determination of the cellular effects of these neurotransmitter receptors.

AB - Adenosine A2a receptors (A2aRs) are highly and selectively expressed in D2-medium spiny neurons (D2-MSNs) that also express a high level of dopamine D2 receptors (D2Rs). However, it was not established how A2aR activity affects D2-MSN excitability, let alone the ion channels involved. We have performed two sets of experiments to determine the potential A2aR agonistic effects on D2-MSN intrinsic excitability and the underlying ion channel mechanism. First, we have used the cAMP-producing, G αs/olf coupled designer receptors exclusively activated by designer drug (Gs-DREADDs) to phenocopy cAMP-stimulating A2aR activation. We found that activation of Gs-DREADD inhibited the inwardly rectifying potassium current (Kir)–a key regulator of MSN excitability, caused a depolarization, increased input resistance, and substantially increased the intrinsic excitability of MSNs such that depolarizing inputs evoked many more action potentials. Second, we have determined that A2aR agonism produced these same excitatory effects on D2-MSN intrinsic excitability and spike firing, although at lower magnitudes than those induced by Gs-DREADD activation; furthermore, these A2aR-triggered excitatory effects were intact in the presence of a D2R antagonist. Taken together, these results clearly establish that in striatal D2-MSNs, A2aR activation can independently inhibit Kir and increase intrinsic excitability and spike and neurotransmitter output; our results also indicate that Gs-DREADD can serve as a broadly useful positive control for neurotransmitter receptors that increase intracellular cAMP levels and hence facilitate the determination of the cellular effects of these neurotransmitter receptors.

UR - http://www.scopus.com/inward/record.url?scp=85060936739&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060936739&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2019.01.014

DO - 10.1016/j.neuropharm.2019.01.014

M3 - Article

VL - 148

SP - 229

EP - 243

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -