AMP-activated protein kinase slows D2 dopamine autoreceptor desensitization in substantia nigra neurons

Wei Yang, Adam C. Munhall, Steven Johnson

Research output: Contribution to journalArticle

Abstract

Dopamine neurons in the substantia nigra zona compacta (SNC) are well known to express D2 receptors. When dopamine is released from somatodendritic sites, activation of D2 autoreceptors suppresses dopamine neuronal activity through activation of G protein-coupled K+ channels. AMP-activated protein kinase (AMPK) is a master enzyme that acts in somatic tissues to suppress energy expenditure and encourage energy production. We hypothesize that AMPK may also conserve energy in central neurons by reducing desensitization of D2 autoreceptors. We used whole-cell patch-clamp recordings to study the effects of AMPK activators and inhibitors on D2 autoreceptor-mediated current in SNC neurons in midbrain slices from rat pups (11–23 days post-natal). Slices were superfused with 100 μM dopamine or 30 μM quinpirole for 25 min, which evoked outward currents that decayed slowly over time. Although the AMPK activators A769662 and ZLN024 significantly slowed rundown of dopamine-evoked current, slowing of quinpirole-evoked current required the presence of a D1-like agonist (SKF38393). Moreover, the D1-like agonist also slowed the rundown of quinpirole-induced current even in the absence of an AMPK activator. Pharmacological antagonist experiments showed that the D1-like agonist effect required activation of either protein kinase A (PKA) or exchange protein directly activated by cAMP 2 (Epac2) pathways. In contrast, the effect of AMPK on rundown of current evoked by quinpirole plus SKF38393 required PKA but not Epac2. We conclude that AMPK slows D2 autoreceptor desensitization by augmenting the effect of D1-like receptors.

Original languageEnglish (US)
Article number107705
JournalNeuropharmacology
Volume158
DOIs
StatePublished - Nov 1 2019

Fingerprint

Autoreceptors
AMP-Activated Protein Kinases
Substantia Nigra
Dopamine
Quinpirole
Neurons
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
Herpes Zoster
Cyclic AMP-Dependent Protein Kinases
A 769662
Dopaminergic Neurons
Protein Kinase Inhibitors
Mesencephalon
protein kinase D2
GTP-Binding Proteins
Energy Metabolism
Proteins
Pharmacology
Enzymes

Keywords

  • AMP kinase
  • D1 receptor
  • D2 autoreceptor
  • Desensitization
  • Dopamine
  • Substantia nigra

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

AMP-activated protein kinase slows D2 dopamine autoreceptor desensitization in substantia nigra neurons. / Yang, Wei; Munhall, Adam C.; Johnson, Steven.

In: Neuropharmacology, Vol. 158, 107705, 01.11.2019.

Research output: Contribution to journalArticle

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