PMID- 22251222
OWN - NLM
STAT- MEDLINE
DCOM- 20120503
LR  - 20120314
IS  - 1471-4159 (Electronic)
IS  - 0022-3042 (Linking)
VI  - 121
IP  - 1
DP  - 2012 Apr
TI  - The T-type voltage-gated calcium channel as a molecular target of the novel 
      cognitive enhancer ST101: enhancement of long-term potentiation and CaMKII 
      autophosphorylation in rat cortical slices.
PG  - 44-53
LID - 10.1111/j.1471-4159.2012.07667.x [doi]
AB  - In this study, we report that spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one 
      (ST101; previously coded as ZSET1446) targets T-type voltage-gated calcium 
      channels in mediating improved cognition in the CNS. We prepared rat 
      somatosensory cortical and hippocampal slices, treated them with 0.01 to 100 nM 
      ST101, and performed immunoblotting and electrophysiological analyses using 
      various voltage-gated calcium channel (VGCC) inhibitors. Treatment of rat 
      cortical slices with a range of ST101 concentrations significantly increased 
      calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation 
      following a bell-shaped dose-response curve, with 0.1 nM ST101 representing the 
      maximally effective concentration. protein kinase Calpha autophosphorylation was also 
      significantly increased by 0.1 nM ST101 treatment. ST101 treatment had a moderate 
      effect on CaMKII autophosphorylation but no effect on hippocampal protein kinase 
      Calpha autophosphorylation in slice preparations. Consistent with increased cortical 
      CaMKII autophosphorylation, AMPA-type glutamate receptor subunit 1 (Ser-831) 
      phosphorylation as a CaMKII post-synaptic substrate was significantly increased 
      by treatment with 0.1-1 nM ST101, whereas phosphorylation of the pre-synaptic 
      substrate synapsin I (Ser-603) remained unchanged. Notably, enhanced CaMKII 
      autophosphorylation seen following 0.1 nM ST101 treatment was significantly 
      inhibited by pre-treatment with 1 muM mibefradil, a T-type VGCC inhibitor, but not 
      with N-type (omega-conotoxin), P/Q-type (omega-agatoxin) or L-type (nifedipine) VGCC 
      inhibitors. Similarly, 0.1 nM ST101 significantly potentiated long-term 
      potentiation in cortical but not hippocampal slices. Enhanced long-term 
      potentiation in cortical slices was totally inhibited by 1 muM mibefadil 
      treatment. Finally, whole-cell patch-clamp analysis of Neuro2A cells 
      over-expressing recombinant human Ca(V) 3.1 (alpha1G) T-channels and treated with 0.1 
      nM ST101 showed significant increases in T-type VGCC currents. These results 
      indicate that T-type VGCCs are direct molecular targets for the novel cognitive 
      enhancer ST101, a potential Alzheimer disease therapeutic.
CI  - (c) 2012 The Authors. Journal of Neurochemistry (c) 2012 International Society for 
      Neurochemistry.
FAU - Moriguchi, Shigeki
AU  - Moriguchi S
AD  - Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku 
      University, Sendai, Japan.
FAU - Shioda, Norifumi
AU  - Shioda N
FAU - Yamamoto, Yui
AU  - Yamamoto Y
FAU - Tagashira, Hideaki
AU  - Tagashira H
FAU - Fukunaga, Kohji
AU  - Fukunaga K
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120203
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Calcium Channels, T-Type)
RN  - 0 (Indans)
RN  - 0 (Nootropic Agents)
RN  - 0 (Spiro Compounds)
RN  - 0 (spiro(imidazo-(1,2-a)pyridine-3,2-indan)-2(3H)-one)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
SB  - IM
MH  - Animals
MH  - Calcium Channels, T-Type/*metabolism
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism
MH  - Cell Line, Tumor
MH  - Drug Delivery Systems/*methods
MH  - Humans
MH  - Indans/*administration & dosage
MH  - Long-Term Potentiation/drug effects/*physiology
MH  - Male
MH  - Nootropic Agents/administration & dosage
MH  - Organ Culture Techniques
MH  - Phosphorylation/drug effects/physiology
MH  - Rats
MH  - Rats, Wistar
MH  - Somatosensory Cortex/drug effects/*metabolism
MH  - Spiro Compounds/*administration & dosage
EDAT- 2012/01/19 06:00
MHDA- 2012/05/04 06:00
CRDT- 2012/01/19 06:00
PHST- 2012/01/19 06:00 [entrez]
PHST- 2012/01/19 06:00 [pubmed]
PHST- 2012/05/04 06:00 [medline]
AID - 10.1111/j.1471-4159.2012.07667.x [doi]
PST - ppublish
SO  - J Neurochem. 2012 Apr;121(1):44-53. doi: 10.1111/j.1471-4159.2012.07667.x. Epub 
      2012 Feb 3.