PMID- 10833508
OWN - NLM
STAT- MEDLINE
DCOM- 20000921
LR  - 20220309
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 275
IP  - 33
DP  - 2000 Aug 18
TI  - TrkB activation by brain-derived neurotrophic factor inhibits the G protein-gated 
      inward rectifier Kir3 by tyrosine phosphorylation of the channel.
PG  - 25082-8
AB  - G protein-activated inwardly rectifying potassium channels (Kir3) are widely 
      expressed throughout the brain, and regulation of their activity modifies 
      neuronal excitability and synaptic transmission. In this study, we show that the 
      neurotrophin brain-derived neurotrophic factor (BDNF), through activation of TrkB 
      receptors, strongly inhibited the basal activity of Kir3. This inhibition was 
      subunit dependent as functional homomeric channels of either Kir3.1 or Kir3.4 
      were significantly inhibited, whereas homomeric channels composed of Kir3.2 were 
      insensitive. The general tyrosine kinase inhibitors genistein, Go 6976, and K252a 
      but not the serine/threonine kinase inhibitor staurosporine blocked the 
      BDNF-induced inhibition of the channel. BDNF was also found to directly stimulate 
      channel phosphorylation because Kir3.1 immunoprecipitated from BDNF-stimulated 
      cells showed enhanced labeling by anti-phosphotyrosine-specific antibodies. The 
      BDNF effect required specific tyrosine residues in the amino terminus of Kir3.1 
      and Kir3.4 channels. Mutations of either Tyr-12, Tyr-67, or both in Kir3.1 or 
      mutation of either Tyr-32, Tyr-53, or both of Kir3. 4 channels to phenylalanine 
      significantly blocked the BDNF-induced inhibition. The insensitive Kir3.2 was 
      made sensitive to BDNF by adding a tyrosine (D41Y) and a lysine (P32K) upstream 
      to generate a phosphorylation site motif analogous to that present in Kir3.4. 
      These results suggest that neurotrophin activation of TrkB receptors may 
      physiologically control neuronal excitability by direct tyrosine phosphorylation 
      of the Kir3.1 and Kir3.4 subunits of G protein-gated inwardly rectifying 
      potassium channels.
FAU - Rogalski, S L
AU  - Rogalski SL
AD  - Department of Pharmacology and Anesthesiology, University of Washington, Seattle 
      98195, USA.
FAU - Appleyard, S M
AU  - Appleyard SM
FAU - Pattillo, A
AU  - Pattillo A
FAU - Terman, G W
AU  - Terman GW
FAU - Chavkin, C
AU  - Chavkin C
LA  - eng
GR  - R01 DA011672/DA/NIDA NIH HHS/United States
GR  - R37 DA011672/DA/NIDA NIH HHS/United States
GR  - DA11672/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Carbazoles)
RN  - 0 (DNA, Complementary)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (G Protein-Coupled Inwardly-Rectifying Potassium Channels)
RN  - 0 (Indole Alkaloids)
RN  - 0 (Indoles)
RN  - 0 (Potassium Channels)
RN  - 0 (Potassium Channels, Inwardly Rectifying)
RN  - 0 (RNA, Messenger)
RN  - 136194-77-9 (Go 6976)
RN  - 42HK56048U (Tyrosine)
RN  - 97161-97-2 (staurosporine aglycone)
RN  - DH2M523P0H (Genistein)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
RN  - H88EPA0A3N (Staurosporine)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*pharmacology
MH  - Carbazoles/pharmacology
MH  - DNA, Complementary/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Electrophysiology
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - G Protein-Coupled Inwardly-Rectifying Potassium Channels
MH  - GTP-Binding Proteins/*metabolism
MH  - Genistein/pharmacology
MH  - Indole Alkaloids
MH  - Indoles/pharmacology
MH  - Lysine/chemistry
MH  - Models, Biological
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Oocytes/drug effects/metabolism
MH  - Phosphorylation
MH  - Potassium Channels/chemistry/*metabolism
MH  - *Potassium Channels, Inwardly Rectifying
MH  - Precipitin Tests
MH  - RNA, Messenger/metabolism
MH  - Receptor, trkB/*metabolism
MH  - Staurosporine/pharmacology
MH  - Tyrosine/*metabolism
MH  - Xenopus
PMC - PMC1276699
MID - NIHMS3463
EDAT- 2000/06/02 09:00
MHDA- 2000/09/23 11:01
PMCR- 2008/01/22
CRDT- 2000/06/02 09:00
PHST- 2000/06/02 09:00 [pubmed]
PHST- 2000/09/23 11:01 [medline]
PHST- 2000/06/02 09:00 [entrez]
PHST- 2008/01/22 00:00 [pmc-release]
AID - S0021-9258(19)62060-0 [pii]
AID - 10.1074/jbc.M000183200 [doi]
PST - ppublish
SO  - J Biol Chem. 2000 Aug 18;275(33):25082-8. doi: 10.1074/jbc.M000183200.