PMID- 20610737
OWN - NLM
STAT- MEDLINE
DCOM- 20100816
LR  - 20220316
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 30
IP  - 27
DP  - 2010 Jul 7
TI  - Interplay of palmitoylation and phosphorylation in the trafficking and 
      localization of phosphodiesterase 10A: implications for the treatment of 
      schizophrenia.
PG  - 9027-37
LID - 10.1523/JNEUROSCI.1635-10.2010 [doi]
AB  - Phosphodiesterase 10A (PDE10A) is a striatum-enriched, dual-specific cyclic 
      nucleotide phosphodiesterase that has gained considerable attention as a 
      potential therapeutic target for psychiatric disorders such as schizophrenia. As 
      such, a PDE10A-selective inhibitor compound, MP-10, has recently entered clinical 
      testing. Since little is known about the cellular regulation of PDE10A, we sought 
      to elucidate the mechanisms that govern its subcellular localization in striatal 
      medium spiny neurons. Previous reports suggest that PDE10A is primarily membrane 
      bound and is transported throughout medium spiny neuron axons and dendrites. 
      Moreover, it has been shown in PC12 cells that the localization of the major 
      splice form, PDE10A2, may be regulated by protein kinase A phosphorylation at 
      threonine 16 (Thr-16). Using an antibody that specifically recognizes 
      phosphorylated Thr-16 (pThr-16) of PDE10A2, we provide evidence that 
      phosphorylation at Thr-16 is critical for the regulation of PDE10A subcellular 
      localization in vivo. Furthermore, we demonstrate in primary mouse striatal 
      neuron cultures that PDE10A membrane association and transport throughout 
      dendritic processes requires palmitoylation of cysteine 11 (Cys-11) of PDE10A2, 
      likely by the palmitoyl acyltransferases DHHC-7 and -19. Finally, we show that 
      Thr-16 phosphorylation regulates PDE10A trafficking and localization by 
      preventing palmitoylation of Cys-11 rather than by interfering with 
      palmitate-lipid interactions. These data support a model whereby PDE10A 
      trafficking and localization can be regulated in response to local fluctuations 
      in cAMP levels. Given this, we propose that excessive striatal dopamine release, 
      as occurs in schizophrenia, might exert differential effects on the regulation of 
      PDE10A localization in the two striatal output pathways.
FAU - Charych, Erik I
AU  - Charych EI
AD  - Pfizer Global Research and Development, Neuroscience Research Unit, Groton, 
      Connecticut 06340, USA. Erik.Charych@Pfizer.com
FAU - Jiang, Li-Xin
AU  - Jiang LX
FAU - Lo, Frederick
AU  - Lo F
FAU - Sullivan, Kelly
AU  - Sullivan K
FAU - Brandon, Nicholas J
AU  - Brandon NJ
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (CPT-cGMP)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Oligopeptides)
RN  - 0 (Palmitates)
RN  - 18263-25-7 (2-bromopalmitate)
RN  - 2ZD004190S (Threonine)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Catalytic Subunits)
RN  - EC 3.1.4.- (PDE10A protein, human)
RN  - EC 3.1.4.- (Phosphoric Diester Hydrolases)
RN  - H2D2X058MU (Cyclic GMP)
RN  - K848JZ4886 (Cysteine)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Cells, Cultured
MH  - Corpus Striatum/cytology
MH  - Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/genetics/metabolism
MH  - Cyclic GMP/analogs & derivatives/pharmacology
MH  - Cysteine/genetics/metabolism
MH  - Cytosol/drug effects/metabolism
MH  - Embryo, Mammalian
MH  - Humans
MH  - Hypoglycemic Agents/pharmacology
MH  - Immunoprecipitation/methods
MH  - Lipoylation/drug effects/genetics/*physiology
MH  - Mice
MH  - Microscopy, Confocal/methods
MH  - Mutagenesis, Site-Directed/methods
MH  - Neurons/drug effects/*physiology/ultrastructure
MH  - Oligopeptides/pharmacology
MH  - Palmitates/pharmacology
MH  - Phosphoric Diester Hydrolases/genetics/*metabolism
MH  - Phosphorylation/drug effects/genetics/physiology
MH  - Protein Transport/drug effects/genetics
MH  - Rats
MH  - Threonine/metabolism
MH  - Transfection/methods
PMC - PMC6632485
EDAT- 2010/07/09 06:00
MHDA- 2010/08/17 06:00
PMCR- 2011/01/07
CRDT- 2010/07/09 06:00
PHST- 2010/07/09 06:00 [entrez]
PHST- 2010/07/09 06:00 [pubmed]
PHST- 2010/08/17 06:00 [medline]
PHST- 2011/01/07 00:00 [pmc-release]
AID - 30/27/9027 [pii]
AID - 3610677 [pii]
AID - 10.1523/JNEUROSCI.1635-10.2010 [doi]
PST - ppublish
SO  - J Neurosci. 2010 Jul 7;30(27):9027-37. doi: 10.1523/JNEUROSCI.1635-10.2010.