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-
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E-mail: Ratushniak.Alex@gmail.com
-

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GeNet.

.

.

106

001(06)+004.032.26 (06)

. . , . . , . .

A. S. RATUSHNYAK, A. L. PROSKURA, T. A. ZAPARA

Design Technological Institute of Digital Techniques,
Siberian Branch of the Russian Academy of Sciences,
Novosibirsk
E-mail: Ratushniak.Alex@gmail.com
STRUCTURAL AND FUNCTIONAL PROPERTIES OF THE NEURON
AND PERSPECTIVES OF COGNITIVE RESEARCH AND
DEVELOPMENT
Abstract
Based on theoretical-experimental analyses, we developed a structural model of
a key element of neuronal input synapse with regard to learning and memory
processes. The conceptual approach comprises the reconstruction of molecular
functional systems that convert the activation of glutamate receptors into structural functional changes of neuronal input regulated by a protein family of small
GTPase and actin-binding proteins. The database and structural model of pyramidal neuron input of the hippocampus were created using GeNet technology.
Interactive graphic representation of numerous facts greatly facilitates the synthesis of experimental data in conceptual knowledge about the principles and
molecular mechanisms of a functioning neuron the basic element of cognitive systems. The use of conceptual models in the development of information
systems can approximate the functional characteristics of the biologic prototype.

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potentiation.html; http://wwwmgs.bionet.nsc.ru/mgs/gnw/genenet/viewer/AMPA.html

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[12]. ,
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001(06)+004.032.26 (06)

117

ISBN 9785726218977

-
.
MAGUK (membrane-associated guanylate kinase) : PSD-95, PSD-93 (Postsynaptic
density protein), SAP97, SAP102 (Synapse-associated protein), Magi-2 ( S-SCAM (Synaptic-scaffolding molecule)) [42]. PSD95 [22]. Sapap (Dlgap 1, 2, 3, 4 (Disks
large-associated protein)) MAGUK , Shank. Begain (Brain-enriched
guanylate kinase-associated protein) PSD95 Dlgap1,
[43]. PRR7 (Synaptic proline-rich membrane protein) NR1
PSD95 [44]. FRMPD4 (FERM PDZ
domain-containing protein 4) MAGUK,
PSD95, , ((4,5)) [45]. NETO1 (Brain-specic
transmembrane protein containing 2 CUB and 1 LDL-receptor class A domains
protein 1) NR2A
[46]. LRFN1 (Leucine-rich repeat
bronectin type III domain-containing protein 1) NR1 GluR1 GluR2
[47].

() ( SH2, SH3 ),
Shank (SH3 and multiple ankyrin repeat domains protein), Homer (Homer
protein homolog 1), Baiap (Brain-specic angiogenesis inhibitor 1-associated
protein), GIT (G protein-coupled receptor kinase-interactor 1).
, , , [35, 48-53]. SH2,
SH3 (10 ) , , ,
SH2 SH3 -
[54].
CAMKII - 118

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001(06)+004.032.26 (06)

119

ISBN 9785726218977

. 2. : ; . () : LRFN1, PRR7,
S-SCAM, NETO1, Dlg1-4, PSD95, Begain, Dlg1, GKAP, SAP97,
FRMPD4, PSD93,GIT1, SHANK, Balap2, HOMER. : p250GAP, RapGEF2? betaPIX , SynGAP, alphaPIX,
Tiam1. : RhoA, CDC42. PTEN . : Kal7, CamkII. nNOS . , : cortactin, DBNL, drebrin, WAVE1. mGluR5, IP3R.

120

001(06)+004.032.26 (06)

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. 3. GluR2: I-CAM 5 ; () : SYNDIG1, TARPs, LRFN1, Dlg4, PSD95, NPRAP.

: GRIP; PICK1; PIP3 -3-.
BRAG2 - . NSF . PKC
alpha . .
. .

[63].
[64], , GluR1-- [65] [66]. ,

.
-, ,
GluR2 GluR3 [67]. [68]. TARPs
(Transmembrane AMPAR Regulatory Proteins) [69]. ,
GluR2/3 ,
GRIP/ABP (Glutamate Receptor Interacting Protein/AMPAR Binding
Protein) NSF (N-Ethylmaleimide-Sensitive Fusion protein) [68, 70]. GluR2 (. 3) ( GRIP-NPRAP-N-cadherin (Neural Plakophilin-Related ARM-Repeat Protein) [71]). N-cadherin, , . PICK1
(Protein kinase C-alpha-binding protein) 001(06)+004.032.26 (06)

121

ISBN 9785726218977

, ,
GluR2-GRIP [72]
- (Protein kinase C ), GluR2;
GluR2/3 [73].
GluR1 .
[74].
31. GluR1- ,
, , [27]. GluR1/2
, GluR2/3.
GluR1 . 4. GluR1 .
SAP97 (SynapseAssociated Protein 97) [68]. GluR1 SAP97 ,
SAP97, - GluR1 [75]. SAP97
[75] aMKII (Ca2+/calmodulin-dependent
protein kinase). SAP97 (A-kinase anchor protein), , , (cAMP-dependent protein kinase catalytic
subunit alpha), (Protein kinase C alpha),
[76-78].
GluR1 ,
S845, , . ,
. .
. ,
GluR1,
, , [25] (. 4,
).
[34].
122

001(06)+004.032.26 (06)

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. 4. , - : , -.
GluR1. (NMDAR) . S845 GluR1--.

2+ ; () : TARPs, SYNDIG1, LRFN1,
PRR7, Dlg1, Dlg4, SAP95, SAP97, PSD95, Begain, GKAP, AKAP,
Dlgap1; I-CAM 5 ; Moesin, P4.1 , ; F-actin ; PKA
; , ( ). . .
.

001(06)+004.032.26 (06)

123

ISBN 9785726218977

GluR1
[34].

,
- -
, Rho
[52, 79].
- Rho. Rac1
, , (. 2,
. 3, 5).
(p21-activated kinase), Rac1 CDC42, - , PIX [85]. , Rac1
[86]. CDC42
-, Homer [87].
RhoA
S-SCAM [53]
(. 2). , -
RhoA [79].
-
,
.
, CAMKII (. 2),
, RhoA [84]. RhoA
ROCK2 (Rho-associated, coiled-coil-containing protein
kinase 2) . - MLCK (Myosin
light chain kinase) (. 5).
2- ,

. ,
, [88]. MLCP
(Myosin light chain phosphatase) . ROCK2 MLCP, - [89].
124

001(06)+004.032.26 (06)

. . , . . , . .

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abcn ao pn q o h

a lpha dPIX (Arhgef6)

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. t t u acn

[80] N oddLa nglois et a l 006;

., 2
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beta dPIX (Arhgef7)

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TIAM 1

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[83] Fleming et a l 1999

.,
[84] Ma et a l 008
., 2

. 5. , :
;
/ ;
. , ; ; RhoA, RAc1 ; PIX, Tiam- GEFs
; MLCK, CaMKII, PAK, LIMK, ROCKII ; CaN,
MLCP .

001(06)+004.032.26 (06)

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ISBN 9785726218977

ROCK2 LIMK (LIM domain kinase),

, [90] (. 5).
Intermediate LTP , ,
Rac1 .
- RasGRF. GEF Ras - NR2A
[91]. , -
RasGRF .
5 .
SynGAP, -, CAMKII GAP Ras [92]. Ras
ERK ,
,
[93]. , SynGAP,
[94]. , SynGAP
[95]. , RasGRF, RhoA, ,
, 10 . ,
,
, GluR1--
[65, 96]. , RasGRF
.
,
/ , . - , ,

, .
-
, 1, ,
, 126

001(06)+004.032.26 (06)

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, -
, . , ,
, , , -,
.
AM2/3
, , , [97]. GluR2/3
, , ,
- , , [32]. 3060 -
2+ 1/2, 200-300%.
- Ca2+
. 2+
0.1 [98, 99]. 2+ - CaMKII , 10 [98],
- 2 .
Rho 2+ /CaMKII
. , Rho
, CaMKII , CaMKII
[98] [100102].
- Rho . RhoA Cdc42 30 , 5 ,
30 [66].
Cdc42, CaMKII [98].
, Cdc42 001(06)+004.032.26 (06)

127

ISBN 9785726218977

30 , Cdc42 , .
Ras
15 [103].
Ras RhoA
. Ras 10 1020
[96]. RhoA 5
.
, Rho ,
CaMKII , CaMKII [98] , . -CaMKII-Cdc42-Pak
,
.
RhoA-ROCK, Rac1/Cdc42-PAK
. - . 5. 2+ /calmodulin
2+ [104,
105]. , calcineurin-colin, RhoA-ROCKmyosin II ,
F-actin G-actin,
,
.
Rac1/Cdc42-PAK , cortactin-Arp2/3-WAVE/N-WASP [106].
,
10 . Rac1/Cdc42-PAK, RhoA-ROCK LIM- colin
F-actin [107].
MLC-, myosin II F-actin
[108] 3 .
3 URL: http://wwwmgs.bionet.nsc.ru/mgs/gnw/genenet/viewer/Early long-term
potentiation.html

128

001(06)+004.032.26 (06)

. . , . . , . .
,
( -)
,
, GluR1/2 , GluR2/3. ? ,
, , , .
. , , ().
-
, , - (-
), ,
. . GluR1
, GluR2 GluR3
SAP97 (DLG1) [109]. GluR2 GluR3
PDZ GRIP1/ABP PICK1
[68].
1
- . , ,
, . () -,
GluR2/3 .
,
- ( ) [110].

001(06)+004.032.26 (06)

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ISBN 9785726218977

-
GluR2/3
, , GluR2/3 ()
- . C-
GluR2, GluR3 PDZ- GRIP1/ABP
AMPA-
. Liprin-
GRIP1/ABP [111]. ,
, . - .
- , GluR2/3,
[112].

TARPs PSD95 (Kato et al.,
2010). - , 5 200 [22].
,
-
[112]. hsp90 [113], rab8
[114], NSF [70]. Hsp90 (heat shock protein 90) , -
. , , hsp90 ,
, [113].
- ,
SNARE, SNAP NSF.
, . ,
SNARE (SNAP receptor) . SNARE , 130

001(06)+004.032.26 (06)

. . , . . , . .
(v-SNARE),
, (t-SNARE). ,
Rab-. , NSF (N-ethilmaleimide-sensitive fusion protein) -SNAP (soluble
NSF attachment protein). NSF ,
GluR2 -  -Snaps
[70].
Rab8 (, ,
) [114].
- (2+ ),
. v-SNAREs , , t-SNAREs 2+ [115]. 2+ IP3 (inositol 1,4,5-tris-phosphate)
IP3 (IP3R)) . IP3 ,
(DAG), PI(4,5)P2 [116], IP3 [117].
. GluR2-- 880 ().
, ()
[116], , , .
1 .
-,
: SAP97 ;
[118].
. , , GluR2/3
.
-, PICK1. PDZ .
, [119]. PICK1
[120] GluR2/3 [119].
001(06)+004.032.26 (06)

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ISBN 9785726218977

PICK1 GluR2-GRIP/ABP, PICK1-PKC-GluR2. - , ,

,
GluR1-- [72].
, , ,
() [37].
- , 2
(, , )
[121, 122].
, , / [123].
- ( , , ) Rab4, Rab5, Rab11, SNAREs: Rab5
/sorting [124], Rab4 Rab11
,


[125]
-
-
,
GluR2/3 [74]. ( GluR1/2 )
GluR1/2 GluR2/3.
132

001(06)+004.032.26 (06)

. . , . . , . .
GluR1/2 GluR2/3.
GluR1/2 .
GluR1
HIP1 (Huntingtin interacting protein),
. HIP1 () 2
. N- , ANTH
2, , PI(4,5)P2. , HIP1
[126]. GluR1 Arc (Activity-regulated cytoskeletonassociated protein), Arc/ARG 3.1,
[127].

, GluR2/3 .
,
. (BFA) [128]. ( (),
()) ,
,
, 1020
[128]. ,

, ,
(, ), , .
,

.
GeneNet
,
, -
() - Vesicles traking, Intermediate-LTP.
001(06)+004.032.26 (06)

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ISBN 9785726218977

Vesicles traking ,
. BFA
ARF1 (. 6).
ARF1
COPI- 1 (1)
[129].
Vesicles traking , , (. 6). , ,
- , [130].
BFA, , ,
1020 [128]. ,
GluR1/2 GluR2/3 ,
, , 310 25 [131]. , BFA GluR2/3
GluR1/2 .
, GluR2/3
(. 6). , GluR1--
[31].
Vesicles traking
:

(prebudding complex, ), , , (. 7).
, 1 , . , 1
134

001(06)+004.032.26 (06)

. . , . . , . .

. 6. Vesicles trafficking. - (): / ARF1; -1 (nascent vesicle); , . TGN

- ; sorting endosome ; synaptic membrane ; extrasynaptic membrane , ; AMPAR -; BFA
. GeneNet
(http://wwwmgs.bionet.nsc.ru/mgs/gnw/genenet/).

, , , ARF,
[132]. 1
001(06)+004.032.26 (06)

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ISBN 9785726218977

. 7. Vesicles trafficking. , : (prebudding

complex) (ERES); COPII (COPII-coated vesicles); COPII , .
Endoplasmic reticulum (). COPII : Sec23/24-Sec13/31/p125. AMPAR -.
GeneNet (http://wwwmgs.bionet.nsc.ru/mgs/gnw/genenet/).

(. 7),
, -, , .
,

[133]. GluR2 -,
[134, 135],
.
136

001(06)+004.032.26 (06)

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,
1
. -,
GluR1/2 [32]. -, GluR1 ,
, - [31],
, , -.
1 , 1 BFA
5060 ( ).
, , BFA 1, - .

- , .
,

.
,
. ,
, .
,
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IV.35.1.5,
108, 136, 120100639.

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receptor and postsynaptic density 95 from mouse brain // J. Neurochem. 2001.
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