PKA/AKAP1 and PP2A/Bβ2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics

Audrey S Dickey; Stefan Strack

doi:10.1523/JNEUROSCI.3159-11.2011

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PKA/AKAP1 and PP2A/Bβ2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics

Journal article

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PKA/AKAP1 and PP2A/Bβ2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics

Audrey S Dickey and Stefan Strack

The Journal of neuroscience, Vol.31(44), pp.15716-15726

11/02/2011

DOI: 10.1523/JNEUROSCI.3159-11.2011

PMCID: PMC3328351

PMID: 22049414

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Abstract

Mitochondrial shape is determined by fission and fusion reactions, perturbation of which can contribute to neuronal injury and disease. Mitochondrial fission is catalyzed by dynamin-related protein 1 (Drp1), a large GTPase of the dynamin family that is highly expressed in neurons and regulated by various posttranslational modifications, including phosphorylation. We report here that reversible phosphorylation of Drp1 at a conserved Ser residue by an outer mitochondrial kinase (PKA/AKAP1) and phosphatase (PP2A/Bβ2) impacts dendrite and synapse development in cultured rat hippocampal neurons. PKA/AKAP1-mediated phosphorylation of Drp1 at Ser656 increased mitochondrial length and dendrite occupancy, enhancing dendritic outgrowth but paradoxically decreasing synapse number and density. Opposing PKA/AKAP1, PP2A/Bβ2-mediated dephosphorylation of Drp1 at Ser656 fragmented and depolarized mitochondria and depleted them from dendrites, stunting dendritic outgrowth but augmenting synapse formation. Raising and lowering intracellular calcium reproduced the effects of dephospho-Drp1 and phospho-Drp1on dendrite and synapse development, respectively, while boosting mitochondrial membrane potential with l-carnitine-fostered dendrite at the expense of synapse formation without altering mitochondrial size or distribution. Thus, outer mitochondrial PKA and PP2A regulate neuronal development by inhibiting and promoting mitochondrial division, respectively. We propose that the bioenergetic state of mitochondria, rather than their localization or shape per se, is the key effector of Drp1, altering calcium homeostasis to modulate neuronal morphology and connectivity.

Phosphorylation - physiology

Dynamins - metabolism

Embryo, Mammalian

Vesicular Transport Proteins - metabolism

Carnitine - metabolism

Green Fluorescent Proteins - genetics

Membrane Potential, Mitochondrial - drug effects

Neurons - ultrastructure

Time Factors

Mitochondrial Proteins - metabolism

Dendrites - physiology

Neurons - physiology

Membrane Potential, Mitochondrial - physiology

Tetrodotoxin - pharmacology

Energy Metabolism - physiology

A Kinase Anchor Proteins - metabolism

Organ Culture Techniques

Cyclic AMP-Dependent Protein Kinases - metabolism

Green Fluorescent Proteins - metabolism

Synapses - physiology

Valine - analogs & derivatives

Rats

Sodium Channel Blockers - pharmacology

Excitatory Amino Acid Antagonists - pharmacology

Mitochondria - metabolism

Hippocampus - cytology

Mutation - genetics

Rats, Sprague-Dawley

Nerve Tissue Proteins - metabolism

Microscopy, Confocal

Animals

Analysis of Variance

Protein Phosphatase 2 - metabolism

Valine - pharmacology

Receptors, Cytoplasmic and Nuclear - metabolism

Details

Title: Subtitle: PKA/AKAP1 and PP2A/Bβ2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics
Creators: Audrey S Dickey - Department of Pharmacology and Neuroscience Graduate Program, University of Iowa, Iowa City, Iowa 52242, USA
Stefan Strack
Resource Type: Journal article
Publication Details: The Journal of neuroscience, Vol.31(44), pp.15716-15726
Publisher: United States
DOI: 10.1523/JNEUROSCI.3159-11.2011
PMID: 22049414
PMCID: PMC3328351
ISSN: 0270-6474
eISSN: 1529-2401
Grant note: R01 NS043254-09 / NINDS NIH HHS NS057714 / NINDS NIH HHS R56 NS056244 / NINDS NIH HHS R01 NS043254 / NINDS NIH HHS R01 NS056244-05 / NINDS NIH HHS NS043254 / NINDS NIH HHS R01 NS057714-02 / NINDS NIH HHS R01 NS057714 / NINDS NIH HHS R01 NS056244 / NINDS NIH HHS NS056244 / NINDS NIH HHS
Language: English
Date published: 11/02/2011
Academic Unit: Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984040531102771

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