4

1. G (GPCRs)
2.
3.
4.

a+
Ca2+
K+

a+/K+-ATP

10
04

(

,
, , )

4.1
4
.


GPCR
Rs
( 40%). 28 %
(
,
,
), 15% ,

,

:
1.

(G
GPCRs).
2.

3.

/.
4.

/.

.



.

1.

G (G prote

ein-couple
ed recepto
ors:
G
GPCRs)
GPCRs

. 2.000 GPCR-likee

1%
.

,
(>1.0000)

,


Richard
d Axel (
Nobeel 2004)




GPCRs. 350

-
GPCRs

, .
150 ,
.
, , , ,
GPCRs . GPCRs
:
30%40% 50
400 GPCRs.
2012 Nobel Brian Kobilka Robert
Lefkowitz GPCRs.

Brian Kobilka (1955 - )

Robert Lefkowitz (1943- )

4.2 Brian Kobilka Robert Lefkowitz Nobel

GPCRs.
1968, Lefkowitz , 1980 Kobilka
.
. 2011, Kobilka .
molecular masterpiece.

GPCRs:
:
.

105

106

( GPCRs) 11-cis-
() trans-.
:
.
:
, , ,
, GABA.
:

,

.
:
GPCRs,
, ,
.
:
. .

GPCRs,
G (, ),
(effectors) (cAMP, I3),

. GPCRs

.
- GPCRs 3
( 4.3 4.4).
,
, , GPCRs
( , , , ),
GPCRs (fMLP-peptide, PAF, ), ,
(, , ),
(LH, TSH, FSH) GPCRs.
( 4.3
), 1 2 ,
.
, NH2 ,
, .
, ,

.
, , , VIP ,
NH2-.
C, ,
Ca2+ GABAB.
2- COOH-.
2 ,
.

1 2 ,
.

4.3 - (, , C) GPCRs
.
Strosberg and Nahmias, G-protein coupled receptor signaling through protein networks,

Biochemical Society Transactions, 2007, 35, 23-28.

107

108

4
4.1 GPCRs ,
.

7
0
2



(((7
70
02
2)))
1: (CCR1- CCR8)
2: (CXR3- CCR7), -8 (IL8-R)
3:
4: (delta, kappa, mu )
(SSTR1-5)
5: (GALR1-3)
6: (CCKAR), , , GnRH
(Gonadotropin releasing hormone)
7: TRH (Thyroptropin-releasing hormone)
8: fMLP (Frmyl Met-Leu-Phe peptide)
9: , , (neuropeptide Y), PRP (prolactin
releasing peptide)
10: (LH, TSH, FSH)
11: (P2RY1-8)
12: (P2RY12-14)
13: (CNR), (LPAR1-3),
,
14: (: PGD2, PGE1, PGE2, PGE3, PGE4,
PGFF, PGI2, A2)
15: (LPAR4-6),
(2R-10)
16: ( 1-5)
17: (5-2, 5-2B, 5-2C, 5-6) , ()
(1, 1, 1D, 2A, 2B, 2C, 1, 2, 3), (D1 D5), (2)
18: (1, 3, 4), (1, 2a, A2b, A3),
(1-5)

GPCRS A

GPCRs .
400 600 7 .
7 - ( 20-25 ),
3 - (loops) 3
.
,
.

4.4 A.
A

-

(
),

2 3

COOH

. D.

Strosberg
S
an F. Pietri--Rouxel, TiPS
and
PS, 1996,
17,
1 373-381.
1.
.

GPC
CR. Mo
orris and
Malbon,
M
Physsiological Re
ev. 1999.

S-S,



.
3

,

G .

2-
,

( ),

.
COOH-
C

Serr Thr,

(PK
KA, PKC
GRK),

1
109

110

.
G -.
B.

A.

4.5 . - (binding pocket).

A C.D. Strader et al, Faseb J., 1989, 3, 1825-32. . ,
, Zubay G, Biochemistry 1998.
A.

4.6 . 3-, .
sp117 3 , (Ser209 Ser212) 5
Phe309 6 . (
). e1-e4: 4 , i1-i3: 4
. D. Strosberg and F. Pietri-Rouxel, TiPS, 1996, 373-381.
. - . Berg et al, 2001.

,
(binding site) .
1. (, , ,
, , )
. -
( sp 113: 113 2- ).

(COO-) (counter-ion)
(2+) . , ,
.
, 3, Ser209 Ser212 V
(...) +,
-.
(binding pocket).
2. , ,
, . ,

.
70 -
GPCRs,
(PARs: proteinases-activated receptors).
,
, - .
- , - ,

.

4.7 PARs (
). , ,
2- , 2- ,
.
Vergnolle N., et al, Proteinase-activated receptors: novel signals for peripheral nerves,

Trends in Neurosci. 2003, 26, 496-500.

3. ,
30 kDa -, ,
-, (FSH: follicle stimulating
hormone), (LH: lutropin), (hCG: human chorionic
gonadotropin), (350-400 ) ,
. 2-
, 20-25 -
-,
. 2- 9 ,
.

111

112

4.8 .
2 (ectodomain) -, 7
(7TM) (IC) 3
C-.
1

8 (IL8)
fMLP-
PAF

(LH, TSH, FSH)

4.9
1

,
-.

,
-.
2 PARs
,
N2-,

.
3
,

2-,
.


1
,
,

2
()

2

,

3

(LH, TSH, FSH)

4.10 GPCRs. ,
.

GPCRs,
. ,
.
GPCRS A

,
.
H1, H2, H3 H4.
H1 , ,
, .
G (Gq), C
PIP2. H1
,
.
, 1
( 2). 1-

. ,
1 .
, .
,
, ,

113

114

, ,
.

4.11 1
, .
, .

, .

H1- , Daniel Bovet

(1933),
, Institut Pasteur . Bovet
1957 Nobel. 1
Benadryl () Johnson & Johnson
1946. ,
( ) .
2
H1 ( 1 , ).
, .
pH (7.4)
, .
2
H1 .
1993 Schering-Plough (.
Claritin). 2 ,
, ,
Zyrtec Pfizer.
3 (levocetirizine)
(desloratadine & fexofenadine) 2 ,
,
.
H2 ,
,
. ,
2 . H2
,
. H2

,
.

4.12 , G ,
. 1, Gaq
, C Ca2+.
2, Gas ,
cAMP. 3 4,
Gai , + Ca2+. R. Ferstl, C. Akdis, L.

O'Mahony, Histamine regulation of innate and adaptive immunity. Frontiers in Bioscience,

2012, 17, 40-53.

o H2 Sir James
Black Smith, Kline and French 1960
Tagamet 1976. ,
- . Glaxo
,
2- (
, 10 , 10%
CYP450 ). 1981
Zantac, 1988,
2-, ,
2- CYP450
. Johnson & Johnson/Merck
Pepcidine.

115

116

H3 (H3R) H4 (H4R) 1988 2000,

, ,

. H3R , H4Rs
, ,
. H3Rs ,
, , , .
H3R
II. H4R
, ,
.
GPCRS A

, 5- (5-R),
GPCRs (5-1, 5-2, 5-4, 5-5, 5-6, 5-7),
5-3 - .
, , ,
, , , , , , ,
. GPCRs 5
,
, .
:
buspirone 5-HT1A.
1986 Bristol-Myers Squibb BuSpar
(GAD, generalized anxiety disorder).
buspirone
,
.
(lecozotan)
5-1, Wyeth
Alzheimer. 5-1
. 2008,
III
.
(sumatriptan) ,
- (DMT), 5--, (5--).

4.13 , , 5HT1D 5-HT1B, .

5-HT1D 5-HT1B,
.

: / , /
/ .
15 min 96%
. GlaxoSmithKline Imitrex
1991 .
(cisapride) 5-HT4,

. (gastroprokinetic)
. Janssen
Pharmaceutica 1980, Prepulsid,
,
. ,
(), .
(agomelatine) 5-HT2C
, , ,
.
Novartis, 2012, Valdoxan,
.
, .
(fenfluramine) 5-HT2C
1972 Ponderax,
.
,
.

4.14 Albert Hofman

(1906-2008) ,



LSD.
100 ,

LSD: My Problem Child.

LSD
(Lysergic
acid
diethylamide)
Sandoz
, Albert Hofmann 1938,

.
,
(ergot),
.
, 1943. LSD
,
.
Sandoz, Delysid, 1947,
. LSD

GPCRs,
,
,

5-HT2A,

5-HT2A

. 5HT2A 5- .

117

118

LSD,

, 5-2 ( D2 ).

Fenfluramine

4.15 ( ) .
GPCRS A

GPCRs
. 5 , GPCRs: D1, D2,
D3, D4, and D5. D1 D5 D1-like, D2, D3 and D4
D2-like. ,
, , , ,
.

(, ),
. ,

Parkinson,
(restless legs syndrome, RLS)1.
1

(),
,
.
,
.
.

(ropinirole) D2, D3,

D4 D2. GlaxoSmithKline
Requip Parkinson Restless Legs
Syndrome (RLS).

SSRI (serotonin specific reuptake inhibitors) .
(apomorphine) D1like and D2-like .
, , .

4.16 , ,
HCl, Parkinson.

.
Parkinson (1951),
(1970), .
.
Parkinson Apokyn, .
Uprima,
Viagra,
.
-,
Alzheimer.

.
(aripiprazole) 2
, ,
,
.
2002, 2004, 2007.
Otsuka Aripiprex.
,
D2 , .
(risperidone)
, D2 ,
, .
,
.
,

119

120

. Johnson & Johnson,

1994, Risperdal.

4.17 D2 ,
5-HT2A, 1 2, 1
. , ,
, ,
.

(lanzapine) ,
5-HT2 D2 .
M3 ,
,
5-HT1, GABAA -.
,
Eli Lilly Zyprexa. Zyprexa
2008 4,7 $.
GPCRS A

- GPCRs
, fight-orflight. , - -.
- : 1 2.
1 Gq ,
C (PLC), PIP2 IP3
(DAG). , 3
Ca2+. , 1-
, , , .
,
, .
(phenylephrine) 1 , ,

,
, ,
, , .
1-
.
(xymetazoline) 1 2-,
. Merck 1961, .
,
.

4.18 ( Sudafed) (
1-
.

(doxazosin) 1-,
Pfizer Cardura,
.
1-
(), .
(prazosin) 1-,
Vasoflex, ,
.
, .
2 (2A, 2, 2C), Gi ,
, cAMP.
.

.
, , ,
.
(clonidine) 2-.
2 Ca2+

.
.
- 1950.

121

122

2010
(attention deficit hyperactivity disorder, ADHD).

, ().
(yohimbine)
Pausinystalia yohimbe (Yohimbe), . 2-,
,
.
. ,
, ,
. ,

, .
2-
, 1-20% 55
.

4.19
Pausinystalia yohimbe, 2-,
, ,
.

- 1, 2 3, Gs
, ,
cAMP. 1- ,
( ),
. 2 ,
, . 3
. -
,
1962, Sir James W. Black - (beta

blockers),

,

20 .

(salmeterrol) 2-

(chronicc obstructivve pulmonary disease, COPD).

.

GlaxoSm
mithKline
1980 19
990 Sereevent.

(salbutaamol)
2-

.
2-

1968
1

Ventoliin.

(
(
200 min)


.

4.20 2-

(Serevent)
(Ventolin),

. 1962
James Black,

Nobbel 1988.

1
123

124

, --,
,


.

4.21
4



, Jame
es Black,
19
962,
20 ,



.

beta blockers,
.

beta blocker,
b
1 2
.



,

,
(5
5-1).

,
.

,
-,

,


.

(
(atenolol)
1 blockker 1976
Ten
normin,



.

,

(metoproolol)

1 blocker

, ,

(carvedilool)

(1, 2) 1

(congestiive heart
failure, CHF).
: Carvil,
Coreg (G
GlaxoSmithhKline), Dilatrend
D
(Roche), Carlooc (Cipla)

2007.

1 2

4.22

(1, 2)
,

1

1-

.
GPCR
RS
A

()

:

, - ,
,

GPCR
Rs.
,

.



().

4.23
4

: / ,

, /
,

. 5
: 1, 2, 3, 4, 5.

4.24
4




5
,
1, 3
5
Gq

C,

2+

3 Ca
C , 2 4
Gi

,
cAMP.
R. Eglena,
a, A. Choppinnb and N. Watsonc,
Wa

Therrapeutic oppo
portunities from
f
muscarrinic recepto
or research, TiPS (2001)
1) 22, 4094
414.

1
125

126

1 ,
, , .
Gq , C
3 Ca2+. 1 AF102B, AF150(S)
AF267B ,
, stress,
tau, .
Alzheimer
.
2 , (sinoatrial node, SA)
(atrioventricular node, AV),
. 2 Gi ,
cAMP, - Ca2+
K+. , 2 ,
(),
(AV node) .

2
Gi
i

Gi

4.25 2 , (SA)
(AV). Gi
+ Ca2+.
,
(AV) .

M3 . Gq
(PLC) Ca2+
.
, 3 ,
, Ca2+ ,
.
(
3) . , 3
.

Muscarinic
M3

4.26 3 ,
,
.

M3 , . ,
, ,
.
(pilocarpine) 3
, 100 . ,
,
, , .

. , ,
3 , Ca2+
. , ,
.
, .

127

128

Pillocarpus miccrophyllus

4.26
4

3

(cilliarry body)

3 ,


,

(trabe
ecular meshw
work),



.

Piloca
carpus microp
ophyllus,

.
.

, Salag
gen

(cevimelin
ne),

3

Evoxac,

3



Sjgrenn.

4.27 3

,


Sjgrren,

Venus Williiams.

(- )
,
Parkinson, , .
Parkinson
,
.

.

.
Parkinson (benzatropine), Cogentin.
,
, ,
Solanaceae
,
.
M1, M2, M3,
M4 M5 ,
Atropa belladonna. "Essential Drugs List",
. "belladonna" ( )
,
,
, .
, .

2 :
(SA)
(AV). (
),
.

, .

.
(scopolamine)
, 1.
Solanaceae,
. Brugmansia, ,
.
,
.
,
, ,
,
, .
,
4.28
.
Albert Ladenburg
1880 ,
330 g

,
.

129

130

,
,
,
,
,

Albeert Ladenbu
urg 1880.

4.29
4

,

Brugmanssia, Angell Trumpet

,

,

,
.

-- Buscop
pan (
Boehringer)

.
,

.




,

4.29
4
-



Buscopan ((
Boehringer)

-



,

(ipratropiuum)
,
, Atrovent,
A
A
Apovent,
Ip
praxa ,


.

,
.
(dimeenhydrinate)
:
,
,
,


, 8-
8
,

,


,

.

,

, Dram
mamine

Diphenhydram
mine

8-chloro-ttheophylline
e

4.30
4
(d
dimenhydrin
nate)

:

, ,

,
8-
.
Dramamine
D

.
GPCR
RS
A

: /
/


,

+

Naa .
,

40
.
,,
,
.
,



,

ACE (anggiotensin-converting ennzyme),

.

GPCRs
G


1, 2,
3, 4.

1

, Gq

C
Ca2++.
,


,
,

, ,

Na+

,

,
, ,

1
131

132

1 , (angiotensin receptor
blockers, ARBs), - . ,
, .
(losartan) T1 ,
1995 Merck.
. 1 ,
.
.

4.30 ,
-,
. (losartan) T1
, 1995 Merck.


GPCRS A

( 20- C).
(COXs) (PGs)
(TXs), (LTs).

PLA2

COX1
COX2

2
Prostaglandin synthases

PGE2

EP1, EP2, EP3, EP4

PGD2

DP1, DP2

PGF2

FP2

PGI2

IP
,

Thromboxane A2

TP

4.31 ( )
( 20 C),
(COX1 COX2). E2, D2, F2a 2,
2, GPCRs, Gs
cAMP
( EP1, EP2, EP3, EP4, DP1, DP2 ), Gq
C (PLC) Ca2+
( FP2 ).

133

134

,
,
. ,
, GPCRs, .
, , sec min,
.

,
1930 Raphael Kurzrok Charles Leib.
PGE2 ,


.
(dinoprostone) 2,
1976 gel
, Pfizer Inc Prostin E2,
2 . 17 ,
25% .
(latanoprost)
F2 Carl B. Camras Columbia University
1996.
. Pfizer Xalatan, ,

. FP .
FP (MMPs),
(uveoscleral drainage).

, .

.

4.32
F2a. Xalatan
, 1,6 $. FP
(ciliary body) ,
(uveoscleral
pathway). ,
, (trabecular pathway)
.

-
. Bengt Samuelsson
1979, , .
5- (, , , ).

shock.
Ca2+, 5- 2 (LTA2).
LTB4, ,
LTC4, ,
LTD4 LTE4. .

4.33 .
Ca2+
2 (PL2).
5--
LTA2. LTB4,
, LTC4. LTC4
- LTD4 LTE4. LTC4. LTB4
, LTD4 LTE4
.

LTB4
,
. LTC4 LTD4
SRSA,
.
, ontelukast afirlukast,
, ,
. montelukast D4

135

136

-, CysLT1, ,
.
GPCRS A

(ADH: antidiuretic hormone:)

,
: / H2, H2
, , /
.

(ADH)

4.34
(osmolarity)

(ADH) . ADH
,

Henle
,
,
, .
,
Henle
,
.

3 GPCRs: V1, V2 V3.

V1a , ,
. Gaq,
C, IP3
Ca2+, .
V1b V3 ,
Gaq C,
ACTH.
V2 , ( Henle
),

.
H2O .

2.

,
(desmopressin)
.
V2

von Willebrand . DesmoMelt,
Stimate, Minirin, ,
(diabetes insipidus)2,
,
( von Willebrand ).

,
,
V1a V1b
ACTH, . , 10
, 1500
. ,
(. Na+).
a+ (),
, , , .
.
, (terlipressin)
V1
. Teripress Glypressin
, shock.

( ""
)
(),
.
V2 , .

137

138

, ,
.

ADH

ADH

4.35 , ,
V2 GPCRs ,
, H2.
, , V1 GPCRs
, C
. J. Finley, M. Konstam, J. Udelson, Arginine Vasopressin

Antagonists for the Treatment of Heart Failure and Hyponatremia, Circulation 118: 410-421
(2008).

4.36
V2
, ,

.

(VRAs,
Vasopressin receptor antagonists)
, (vaptan
drugs),
2009.


(SIADH, syndrome of inappropriate
antidiuretic hormone secretion),

. ,
,

,
. SIADH,

,
,

,
.
(tolvaptan)

V2,
Otsuka Pharmaceutical Co, 2009.
Resodim
Na+.

GPCRS A

, Papaver
somniferum Sertrner, 1803. 1827 Merck,
Darmstadt,
.
,
, ,
, , .
GPCRs
. , (1, 2, 3)
, (1, 2), (1, 2, 3)
,
.

, ,

,
.

139

140

1 , 2
, .
.
.
( ),
, ,
. ()
, ,
.
, ,
, .
.
:
(fentanyl).
,
.
,
, , .
,
,

. .

4.37
GPCRs


.
,


Gi
. cAMP

Ca2+
.
,


+
+
.

.

, ,
,
.

. 1832 Pierre
Robiquet.
: , ,
,
.
: , (naloxone) ,
, 17 .
.

. ,
. 1-3
, , .
1960 Sankyo Narcan.

17

4.38 , 17
.
.
GPCRS A
TH GnRH (GONADOTROPIN RELEASING HORMONE)

GnRH, ,
. -
, GPCRs , GnRHRs,
. GnRH
, Gq PLC, 3 Ca2+.
PKC,
: (LH)
(FSH) .
, , .

141

142

GnRH.

GnRH
,
,
(
).

GnRH ,

,
LH FSH.

LH FSH
.
4.39 GnRH ,
,
GPCRs , LH FSH,
, .

4.40 GnRH , Gaq

PLC. PKC,
(LH, FSH).

GnRH
, , GnRH, , down
regulation , , LH
FSH, , .
.
GnRH
. 8-14 ,
9-14 . ,
,
35-70 . GnRH
- :
.
,
. ,
.
transsexual ,
trans women.
in vitro fertilisation (IVF),
FSH.
GnRH, -,
FSH ,
(hCG), 3.
,
.
GnRH
GnRH, 6 10.
.
FSH LH. ,
10 , FSH LH,
down-regulation .
700 GnRH: leuprolide (Lupron, Eligard), buserelin
(Suprefact, Suprecor), histrelin (Supprelin, Vantas), goserelin (Zoladex), and deslorelin
(Suprelorin, Ovuplant).
4.41 leucopride (Lupron)
GnRH .
,
GnRH,
,
.
in vitro (IVF).

, LH FSH .
, .
, GnRH
LH FSH. ,
GnRH . GnRH
.

143

144

GnRH GnRH,
. GnRH
GnRH ,
LH FSH. LH
,
.
GnRH, --,
,
, .
,
(castration)
.
GnRH
GnRH.
GnRH
LH
FSH in-vitro (IVF).

hCG -
. GnRH,
Cetrorelix Ganirelix
Cetrorelix GnRH.
-
(,
). , cetrorelix
, GnRH ,
LH FSH.

. LH
hCG
.

4.42 To cetrorelix (Cetrotide)

Serono
LH

FSH
in-vitro (IVF).

G
GPCRs

( 20

,
,

,
,
,
, ,

),

.
>277
,

,
/
.

((1155))
1
27141
(15):
,
,,
(VIP),

(),
(CRH),

(GHRH),PACAP(piituitaryaden
nylatecyclaseactivatingpopypeptidee)
2EGF
NH
H2:EGFmoduleco
ontainingmu
ucin
likerecceptors(EMR
R),leukocyteecellsurfaceeantigenCD97
,calciumin
ndependent
latrotoxin
9
recepto
ors

vasoacttive intestinnal peptide (VIP)
:
VPAC1 ( , ,

, )
VPAC2 ( ,

, ,
, ,

, ).

Gs
,

c
cAMP,



VIP
P.


VPA
AC1 VP
PAC2

.
G
GPCRs

C

GPCRs

(mGlu2//3) GABA
(GAB
BAB),

GABA
G
1

GABA2.

G
.

CC

((2222))

GA
ABAB,
Ca2+,T1
1,

1
145

146

2. (Ligand-gated ion channel receptors)

- - .
2 : cys-loop ,
5 (2)
( , GABAA
GABAC, 5-3),
, 4 ( NMDA,
AMPA ).

4.43 - GABAA. 5
(2)

(), , .

- ,
,
: a+ Ca2+ , 5-3
, Cl- GABAA, GABAC .
(depolarization)
-. , 53 ( NMDA, AMPA ),
.
(hyperpolarization) . GABA, GABAC .
, msec,
(fast responding receptors),
G, ,
G, (effector)
.
-
O (subunits) - (4 5)
: 4 , - , .

4 EN (-V). 20-30
-, .
( 20) .

4.44
5
2 GABAA.
4

(1, 2, 3, 4). G.B. Smith

and R.W. Olsen, TiPS 1995, 16, 162-167.

( ,
)
( 5,6 ). ,

. (Pro)
.
,
(Ser248, Ser254, Ser256, Ser262) ,
(non competitive blockers)*
( 3.14).
(. ,
, )
(),

, .

, .

(D).
.
. J-P.

Changeux et al, Achetylcholine receptor: an allosteric protein, Science, 1984, 225, 13351344.

147

148

4.45 . -.
4 (1-4), 2030 -
. .
. 2

. H.R. Arias, Brain Res.Rev., 1997,

25, 133-191.

4.46
, 2
Ch
.
CPZ (),
(-),
TID
Arias H.R., Brain Res. Rv., 1997, 25, 133-91.

4.47 .
.
(high affinity site) . 30
, (low affinity sites)
. J-P. Changeux et al, Science, 1984, 225, 1335-1343.

1 E 2 ,
.

: GABAA,
Cl-, ,
Na+ +. - ,
(driving force) .
- ,
cAMP.
.

4.48
. Hucho F. et al, TiBS, 1994, 19, 383-387.

AMINOTEIKO AO (NH2-TERMINAL). ,
. (2)
GABA 5-3,
-, . .

, .
- GABA
.
GABA
. GABA

.
(Cys139
Cys153), S-S. Cys-Cys
,
.

, . .
, , ,
( - -).

(2).

149

150

(COOH-TERMINAL).

G,
,
-

.

4.49
. Cys138- Cys152
Cys198-Cys209, .
Laube B. et al, TiPS, 2002, 23, 519-527.

.
,

.
,
. ,

.

.

2-3 nm .

. 2 .

- .

4.50 () ,
.
,
.
.
.
() 2
. Unwin N., Achetylcholin receptor channel imaged in the open

state, Nature, 1995, 373, 37-43.

.

.
, 2
.
.
. .
,
.
, 2.
2 .
.
2 ,
.

.

prefilter

M2

M2

M2

4.51 () 2 .
( )
.
.
() 2 .
2 . (): 2
. .
(): 2
. 2
.
( )
,
. Unwin N., Achetylcholin receptor channel imaged in the open

state, Nature, 1995, 373, 37-43.

151

152

-
- .
, , NMDA
(--D-), AMPA (--3--5--4 ) .
NMDA ,
.
, NMDA

. NMDA

LTP ( ).

, Ca2+. NMDA
.
NMDA :

.
AMPA NMDA.
NMDA Mg2+ ( Zn2+),
.
, Na+.
Mg2+
NMDA.
NMDA a+ Ca2+.

4.52 NMDA, ,
.
NMDA ( Mg2+ ) (
Na+). , Mg2+
NMDA a+ Ca2+.

NMDA
NMDA -,
NR1 2 NR2A, NR2B, NR2C NR2D (
NR1-NR1-NR2A-NR2A). 3 (1,
3 4). 2
. 2 2 .
2 , ,
S1, S2, COO- ,
.
2 . 2
-,
1 3 .
Q/R/N .
(Q), (R) ,
() DA.

4.53 NMDA.
(NR1-NR4). 3 (1, 3
4). 2 2 .

NMDA, -,
.
NMDA PCP
(phencyclidine, ) (angel
dust) .

4.54
NMDA.

153

154

3. (Receptors tyrosine kinase)

.
.
. ,

.
,
.

: (EGF: epidermal growth factor),
(PDGF: platelet-derived growth
factor), (NGF: nerve growth factor), .

(growth factor receptors).
.
-
: ( EGF, NGF, PDGF)
( ).
/
,
. (
) ,
(
) .
, ,
.
H EGF.
,
.
EGF ,
.

4.55 (EGF) ,
, .
(Protein Tyrosine Kinase) ,
. . J. Schlessinger, TiBS, 1993, 18, 273-275.

H PDGF.
5 ( )
(immunoglobulin-like domains).

,
(kinase insert region).
, -.
4.56
PDGF (
).
.

. -
,
, GAP (GTPase activating
protein), 3- C- (PLC-).
85
/ -
-. W.J. Fantl et al, Annu. Rev.

Biochem., 1993, 62, 453-481.

FGF (fibroblast growth factor:

).
3 ,
( ).
.
VEGF (vascular endothelial growth factor:
).
,
.
NGF (nerve growth factor:
). NGF (neurotrophins)
neurotrophin receptors family.
trk, trk trkA. 2
(Ig-like domains) 2
(FNIII).


,
. .

155

156

4.57 - - PDGF.
PDGF, - , , .

(PDGF: platelet derived growth factor)
,
,
, .
,
,
PDGF .

/ -

. - -,
S-S 22.
(-precursor),
Golgi,
, ,
.
- ,
. 15-20
, . -
.
,
-, -
.
-
, .
.

4.58
.
,
.


.

RTKs
trans .
, SH2 ,
.
, -.

: C, (src ..), p120 GAP ( GTP
activating protein), - (Grb2, Shc, IRS), (Syp
.) 3-.

4.59 trans- Tyr (Y-) ,

(SH2 PTB),
.

581

-P

-P

Src

Grb2

SOS

4.60
(Src, Grb2,
P85 3-, GAP
PLC)

(-) RTK.

157

158

4.
.
,
.
.

, -
, DNA-binding C- .
DNA binding
DNA, (nuclear localization)
. 66
. n2+ 4 .
DNA - C DNA-binding.
- .
. trans-,
(AF1).
C- .
(hormone-binding domain), trans-
(AF2), trans-,
. AF2
trans-
.

1. (.. ).
2. (.. D3).
3. (.. ).
4. , .
DNA
1. . ,
(-)
, .
2. .
,
(-) ,
.
3. ( )
DNA .
4. ( )
DNA .

, ,
. , . ,
,
chaperone (
shock), Hsp90, Hsp70, Hsp56 (Hsp: heat shock
protein).
.
Hsp90, . Hsp79
sp90 .
,
DNA hormone responsive elements (HREs)

4.61 .

Hsp7

Hsp7

4.62 .
: D (hormone binding domain), , DBD (DNA binding
domain) DNA NTD (nuclear
translocation domain), .

159

160

Zn2+-Cys4

H
DNA

DNA

4.63
HRE
DNA DNA
binding .
, (b)
Zn2+Cys4,
DNA,

HRE.
(c) Zn2+
,
4 ,
DNA
.
DNA
(RE),
(d),

,
4
:
5-AGGTCA-NNNN-TGACCT-3

T , D3
3
,
.
1.
,
. . 3.
2.
,
, . . 9-cis-
1 ().
3. .
.

. (RAR RXR), 3 (3R)
D3 (VDR)
(heat shock proteins). ,
HRE DNA, , (repressors)
.
.

, 4.64.

4.64 , D3 3.

,
, ,
. .
(Glucorticoid resistance)
,
, .
,
, ACTH
(),
Cushing.
. T

, - (GR), ,
-, trans-
1, .
(5-10%) .
- GR,
GR, .

,
a+, Cl- 2 K+, Ca2+
. ,
.
.
.

161

162

, .
.

cAMP.
cAMP

.

,
.
,
LBD.
- tamoxifen. -

,
.
D3
D3 7- .
, , D3.
1,25-D3.
.
VDR (Vitamin D Receptor)
: , , 1,25-D3
. VDR
:
1. DBD
,
.
2. ,
LBD
.
-
VDR retinoid X receptor (RXR). RXR
T3R, VDR RAR. VDR
RXR LBD . ,
LBD
,
.
VDR RXR ,
,
.
, D3 -,
tamoxifen, , , ...

. , VDR ER
.
-
-
.
,
, a+, + Ca2+. ,
0,5
msec. ,
2 msec .
- :
( , ),
( ) (
).
,
.
.

.
: a+, + Ca2+
. , a+
12 .
Ca2+ Ca2+ 1000 .

4.65
-
Na+ Ca2+.
-
Na+ Ca2+

4
.

163

164

-
- a+, + Ca2+, ,
(review, Catterall 1995). , 4
, (
Na+ Ca2+)
( +).

4.66 - + . - +
4 .

6 (S1-S6),
-. S4
, SS1 SS2
.

.
.
4.67 -.
6
(S1-S6),
-. S4
,
SS1 SS2
.

,
. S4
/
. S4
.
, (
msec) .

. (
)
. S4
, .
S4 - .

4.68 - Na+ (
) .

msec,
( ). , ,
,
-.

-
-
a+:
, .
, .
Na+ ,
- -.
.
200 .
.

165

166

.
.
Ion passage and ion selectivity

4.69 Na+,
.

- N+
- a+
(),
.
(puffer fish) .
,
.
- Na+
(10nM) Na+
100 .
, ,
( ),
50 .

.

a+
, a+ .

a+
.

- Ca2+
Ca2+ : L
(large ), , .
Ca2+ L,
, -
Ca2+ Ca2+- Ca2+
Ca2+ 100 nM
, 10. Ca2+ ,
-
.

4.70 - Ca2+ L (LTCCs)

1 (2-,
). 1 (C1.1, C1.2, C1.3,
C1.4) .
1 (I, II, III, IV)
6 .
C1.2
(Thr1066 Tyr1066), -.

Ca2+ L- (Ca2+ blockers) :

167

168

1. 1,4- (DHP), . .
2. (PAA), . .
3. (), . .
Ca2+

.
- +

- +
+
. 60 -
+. , +
3 :
1. + (Transient outward K+ channels):
Ito.
Na+ .
+
( 3.42).
4--.
2. + (Delayed rectifier K+
channels): IKr. ,
100-300 msec.
Ca2+ L
+.
, +
,
, + . ,
,
+ . +
+ (kr)
.

+. kr -.
3. + (Inward rectifier K+ channels): IKi.

+ (-95mV) ki
+ .

, +.
Iki : 4 ,
, - . -

( 4.71). .


4.71

Ito
+ (Ito, Ikr, Iki)
IKr
IK
.
Ito
Na+.

+

IKi
.
,

100-300 msec.
Ca2+
L
+ IKr.
+ (-95mV)
ki + .

4.72


+.
. +

,

(v)
(mink),

.
. +
4
(
).
-
6
.
C. Ta

+ (Inward rectifier K+
channels)
4

- .

169

170

. Na+/K+ ATP
Na+/K+-

Na+ K+ , 3 Na+
2 + ,
Na+
10 , K+ 20
.

, ,
.
(5mV)
20 mV.

-
b-

4.73 4
Na+/K+- (),
().
. ()
Digitalis purpurea, William Withering ()
.

( ),
, ,
Na+
.
Ca2+ .
Ca2+ ,

Ca2+- a+/Ca2+
.
Na+/K+- Na+
a+/Ca2+, Ca2+
.
, .

.
, , ,
.
.
(neurotransmitter transporters)

:
,
,
, .
:
Na+/Cl-- ,
Na+ Cl-
+- ,
+
.

4.74 , .

171

172

4
Na+/Cl--

Na+.
,
(uptake).
, +-
, +.

Susan Amara and Mark Sonders, Drug and Alcohol dependence, 51, 87-96, 1998.

,
GABA (GAT1) (Guastella et al, 1990)
() (Pacholczyk et al, 1991).
cDNAs
(DAT) (SERT).
4 GABA, 5
(GLYT1-5), , DAT, SERT
. Na+/Cl--
12 , 2- COOH 3 4,
.

4.75 ()
(). Susan Amara and Mark Sonders, Drug and

Alcohol dependence, 51, 87-96, 1998.

+-
. ,
+, (--)
. ,
cDNA .
(VMAT1
VMAT2) (VAChT).
12 , 2- COOH-
1 2,
.


:
,
(SSRIs, selective serotonine reuptake inhibitors): (Prozac),
, .
, ,
: : ,
, .
,
.
(DAT)
.
GABA GAT-1 (Gabatril),
GABA
.

. -
, ,
. ( ACh
) :
(AChE), (Ch)
,
.
AChE , ,
S-S, 70-80 kDa, .
3.47 AChE
, (G) (A) (
). AChE
.
, ACh
AChE (G1, G2 G4). 12 ACh
.
H ChE :
14.000 ACh /sec .

173

174

4.76 : ,
. Taylor and Radic, Annu. Rev. Toxicol. Pharmacol. 1994, 34, 281-320.

1854
Philipe de Clermont (1830-1921), Calabar,
Physostigma venenosum Calabar .
.
10 (), -. Clermont
,
,
.

1877,

, ,
.

Physostigma
venenosum

,
AChE, (,
).


,
(DPF) .

Birjinni 25
1988,
. LD50
( !) 10g kg-1.
Aum, 12 5500
.
, ,
;

( msec) .
.

. ,
DFP (-) (---)
.
,
.

4.77 DIPF
.

.

, , .,
(5-, ). ,
s (Inhibitors of monoaminoxidases)
(
). :

175

17
76

-,

,

,
-,

,
,
,

P
Parkinson,

Alzheimer,

- ..

.
,

.


,

,

,
, ,

.


cheese efffect



(.
, ,
)).

.

(Mitogeen-activatedd protein kinases)

k


.
,
, ,
,

s



.



.

MEKK

MEK kinnase

MEK
MKK
SEK
SKK
JNKK

MAPK/E
ERK kinasee
MAPK kinase
k
SAPK/E
ERK kinase
SAPK kinase
k
JNK kinnase

MAPK
ERK
JNK
SAPK
CSBP
BMK

Mitogenn activated protein

p
kinaase
Extracelllular signall-regulated kinase
k
Jun-N-teerminal kinaase
Stress-acctivated pro
otein kinase
Cytokinee suppressiv
ve anti-inflaammatory ddrug binding
g protein
Big mitoogen kinase

ERK
K/MAPK

,

.
,
.

p38 ( SA: stress activated
protein kinase) .
, APKs
.
,
. ,

( 500),
.
,
p38, ERK1, 2, 5 JNK.
p38
s p38.
48 p38 15 .
p38 (, UV, ).

-, , IL-1
TNF- LPS.
p38 IL-1 TNF-, p38
- ,
,
. p38, Vertex745
RPR200765A (

), SB235699 (
, .....).

-,
4.78 p38.

. ,


,

106.

( .4.78),

.
p38 ( p38
p38)

177

178

.
(high afctivity)
(low activity). p38
,
(nM)
, mM .

1 2
p38, . s
s ( ). ,

.
1 2
.
.
(PD98059, PD184352, U0126)
(Ro092210,
LLZ16402).

4.79 ,
in vitro
.

10

.



.

.

DNA DNA
:
- DNA,
- DNA

- DNA.
DNA,
.
DNA.

4.80
DNA : /
DNA, / DNA
/ DNA.

Camptotheca accuminata.
1970 .
15 TopI,
.

179

180

4.81
,
.
DNA
DNA
.

Mandragora officinarum
TopII DNA.
DNA
.

(DNA, RNA)
.
,
DNA ,
, .
Streptococcus verticillus.
2 2.
, (Fe2+
Cu2+).
DN, 2 Fe2+.
2 ( DTT)
-Fe2+ -
Fe2+ 2 ,

DNA.
DNA
(3- 4-2)
(2-2 3) 5. DNA
DNA, (linker domain) .

in vitro
G2 , ,
DNA, .

4.82 .

4.83
DNA. Chen and Stubbe, Current Opinion in Chemical Biology, 8, 175-181,
2004.

181

182

,
DNA
DNA
A .

DN
NA (MGM))
.

CP
PI (cyclopropylpyrroloiindole),

(bizelessin),

DNA (),


(hot spoots).

DNA

. ,

.
,


.

4.84
4
, DNA
D
(
).

(
, ,, ))

DNA
A. 5- (5-FU)

RNA
A
.

5-

(5-FU)

5-

(
)

5-
)
(

4.85

5--

, , 5 .
5
, , 5-- (5-FU)
.
5-FU
( ) (FdUMP,
-), .
F-C C-H
5 5-FU . FdUMP ,
(5,10-- )
. FdUMP
- ( )
. DNA ,

.
5-FU RNA,
DNA.


,
.

4.86 5-FU
FUR: -
FUDP:
FUMP:
FUTP:
FUdR:
FdUDP:
FdUMP:
FdUTP: o
PRPP: 5--1-.

5'- (FUMP) :

183

184

/ 5-FU (FUR)
FUMP .
) 5-FU 5--1-
(PRPP)
FUMP.
F-UMP
RNA.

(
) 5--5'--2'- (F-dUMP).
H 5-FU 5-FUdR
F-dUMP . FdUMP .
F-dUMP
(). F-dUMP
5-FU, 5-FUdR,
F-dUMP .
5-FU DNA RNA.
5-FU, F-dUTP dUTP (
)
DNA ( ).
F-dUTP dUTP .
RNA
RNA.

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