PMID- 25009260
OWN - NLM
STAT- MEDLINE
DCOM- 20140909
LR  - 20211021
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 34
IP  - 28
DP  - 2014 Jul 9
TI  - The role of Pak-interacting exchange factor-beta phosphorylation at serines 340 and 
      583 by PKCgamma in dopamine release.
PG  - 9268-80
LID - 10.1523/JNEUROSCI.4278-13.2014 [doi]
AB  - Protein kinase C (PKC) has been implicated in the control of neurotransmitter 
      release. The AS/AGU rat, which has a nonsense mutation in PKCgamma, shows symptoms of 
      parkinsonian syndrome, including dopamine release impairments in the striatum. 
      Here, we found that the AS/AGU rat is PKCgamma-knock-out (KO) and that PKCgamma-KO mice 
      showed parkinsonian syndrome. However, the PKCgamma substrates responsible for the 
      regulated exocytosis of dopamine in vivo have not yet been elucidated. To 
      identify the PKCgamma substrates involved in dopamine release, we used PKCgamma-KO mice 
      and a phosphoproteome analysis. We found 10 candidate phosphoproteins that had 
      decreased phosphorylation levels in the striatum of PKCgamma-KO mice. We focused on 
      Pak-interacting exchange factor-beta (betaPIX), a Cdc42/Rac1 guanine nucleotide 
      exchange factor, and found that PKCgamma directly phosphorylates betaPIX at Ser583 and 
      indirectly at Ser340 in cells. Furthermore, we found that PKC phosphorylated betaPIX 
      in vivo. Classical PKC inhibitors and betaPIX knock-down (KD) significantly 
      suppressed Ca(2+)-evoked dopamine release in PC12 cells. Wild-type betaPIX, and not 
      the betaPIX mutants Ser340 Ala or Ser583 Ala, fully rescued the decreased dopamine 
      release by betaPIX KD. Double KD of Cdc42 and Rac1 decreased dopamine release from 
      PC12 cells. These findings indicate that the phosphorylation of betaPIX at Ser340 
      and Ser583 has pivotal roles in Ca(2+)-evoked dopamine release in the striatum. 
      Therefore, we propose that PKCgamma positively modulates dopamine release through 
      beta2PIX phosphorylation. The PKCgamma-betaPIX-Cdc42/Rac1 phosphorylation axis may provide 
      a new therapeutic target for the treatment of parkinsonian syndrome.
CI  - Copyright (c) 2014 the authors 0270-6474/14/349268-13$15.00/0.
FAU - Shirafuji, Toshihiko
AU  - Shirafuji T
AD  - Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, 
      Kobe 657-8501, Japan.
FAU - Ueyama, Takehiko
AU  - Ueyama T
AD  - Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, 
      Kobe 657-8501, Japan.
FAU - Yoshino, Ken-ichi
AU  - Yoshino K
AD  - Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, 
      Kobe 657-8501, Japan.
FAU - Takahashi, Hideyuki
AU  - Takahashi H
AD  - Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, 
      Kobe 657-8501, Japan.
FAU - Adachi, Naoko
AU  - Adachi N
AD  - Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, 
      Kobe 657-8501, Japan.
FAU - Ago, Yukio
AU  - Ago Y
AD  - Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, 
      Osaka University, Suita, Osaka 565-0871, Japan.
FAU - Koda, Ken
AU  - Koda K
AD  - Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, 
      Osaka University, Suita, Osaka 565-0871, Japan.
FAU - Nashida, Tetsuaki
AU  - Nashida T
AD  - Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, 
      Osaka University, Suita, Osaka 565-0871, Japan.
FAU - Hiramatsu, Naoki
AU  - Hiramatsu N
AD  - Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, 
      Osaka University, Suita, Osaka 565-0871, Japan.
FAU - Matsuda, Toshio
AU  - Matsuda T
AD  - Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, 
      Osaka University, Suita, Osaka 565-0871, Japan.
FAU - Toda, Tatsushi
AU  - Toda T
AD  - Division of Neurology/Molecular Brain Science, Kobe University Graduate School of 
      Medicine, Kobe 650-0017, Japan, and.
FAU - Sakai, Norio
AU  - Sakai N
AD  - Department of Molecular and Pharmacological Neuroscience, Graduate School of 
      Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
FAU - Saito, Naoaki
AU  - Saito N
AUID- ORCID: 0000-0003-3389-1367
AD  - Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, 
      Kobe 657-8501, Japan, naosaito@kobe-u.ac.jp.
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 (Phosphoproteins)
RN  - 0 (Rho Guanine Nucleotide Exchange Factors)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.1.- (protein kinase C gamma)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Animals
MH  - Binding Sites
MH  - Corpus Striatum/*metabolism
MH  - Dopamine/biosynthesis/*metabolism
MH  - Dopaminergic Neurons/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - Protein Binding
MH  - Protein Kinase C/*metabolism
MH  - Rats
MH  - Rho Guanine Nucleotide Exchange Factors/chemistry/*metabolism
MH  - Serine/chemistry/*metabolism
PMC - PMC6608353
OTO - NOTNLM
OT  - Cdc42
OT  - PKC
OT  - Parkinson's disease
OT  - dopamine
OT  - phosphoproteome
OT  - betaPIX
EDAT- 2014/07/11 06:00
MHDA- 2014/09/10 06:00
PMCR- 2015/01/09
CRDT- 2014/07/11 06:00
PHST- 2014/07/11 06:00 [entrez]
PHST- 2014/07/11 06:00 [pubmed]
PHST- 2014/09/10 06:00 [medline]
PHST- 2015/01/09 00:00 [pmc-release]
AID - 34/28/9268 [pii]
AID - 4278-13 [pii]
AID - 10.1523/JNEUROSCI.4278-13.2014 [doi]
PST - ppublish
SO  - J Neurosci. 2014 Jul 9;34(28):9268-80. doi: 10.1523/JNEUROSCI.4278-13.2014.