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PDE11A negatively regulates lithium responsivity in mice possibly due to an interaction with AKT/PKB (1144.8)
Author(s) -
Kelly Michy,
Pathak Geetanjali,
Hartman Alexander
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1144.8
Subject(s) - lithium (medication) , chemistry , medicine , endocrinology , protein kinase b , biology , biochemistry , signal transduction
Lithium is a first line mood stabilizer for patients with bipolar disorder, but for unknown reasons approximately half of all patients do not respond to lithium. Lithium responsiveness in patients with bipolar disorder has been genetically associated with single nucleotide polymorphisms (SNPs) in Phosphodiesterase 11A (PDE11A), a unique enzyme that breaks down cAMP and cGMP only in the hippocampus. These PDE11A SNPs are intronic; therefore, the objective of this study was to determine if decreasing PDE11A expression was sufficient to increase lithium responsivity in mice. We measured PDE11A expression by in situ hybridization and Western blot in the hippocampus of inbred mouse strains known to respond well (C57BL/6J), moderately (129S6) or poorly (Balb/cJ) to lithium. PDE11A mRNA and protein levels were lowest in C57BL/6J mice, the strain most responsive to lithium, and highest in Balb/cJ mice, the least responsive strain. Consistent with these observations, PDE11A KO mice given 0.4% lithium chow for 3 weeks exhibited greater lithium responsivity relative to wild‐type littermates in tail suspension, an anti‐depressant predictive assay, and in amphetamine hyperlocomotion, an anti‐manic predictive assay. Lithium does not directly affect PDE11A catalytic activity; however, in vitro experiments suggest that PDE11A may influence lithium responsiveness due to an interaction with AKT, an enzyme that is required for lithium’s behavioral effects. AKT is predicted to phosphorylate PDE11A at several residues, including serines 117 and 162. Phosphomimic mutations of serines 117 and 162 shift the subcellular distribution of PDE11A away from a punctate, membrane enriched compartmentalization towards a more diffuse, cytoplasmic localization. Together, these findings suggest that PDE11A negatively regulates lithium responsiveness by inhibiting the activation of AKT but that AKT can feed back and release this brake by phosphorylating PDE11A, thereby removing PDE11A from the membrane. Grant Funding Source : Research supported by a PhRMA Foundation and the University of South Carolina