H 2 receptor

The gene and cDNA encoding the H2 receptor have been identified in several species including man (Gantz et al. 1991a,b; Ruat et al. 1991; Traiffort et al. 1995). Using the polymerase chain reaction (PCR) with degenerate oligonucleotides based on the homologybetween various GPCRs, and canine gastric parietal cDNA, Gantz et al. (1991b) obtained the first gene

H1_HUMAN -------MSLPNSSCLLEDKMCEGN

H3_HUMAN MERAPPDGPLNASGALAGDAAAAGG

KT T MAS PQLME F C L DlTACKIT ARGFIAAWTAV T INLIL STRV1

/VLS TICLVTVGL N /VLAVLILITVAGN \L M AL L I va^bl|

Hfmslvafaimlgn

/VLS TICLVTVGL N /VLAVLILITVAGN \L M AL L I va^bl|

Hfmslvafaimlgn

Sec.Struct

TM I

H1 HUMAN

V

R S

E

R K

|h

T V

gbl

Y I VS

|SVA|

L ibg

AV

H2 HUMAN

V

GL

N

RR

L R

N L

tbc

1 VS

laitD

L L L G

L L

H3 HUMAN

F

VA

D

S S

L R

TQ

NNF

Il l n

L A I s|

F lbg

AF

H4 HUMAN

F

VV

D

KN

MI

H I

sSy

If l n

L A I s|

f F VG

V I

Sec.Struct

H1_HUMAN H2_HUMAN H3_HUMAN H4_HUMAN

Sec.Struct

DRYRlVQQPLR D RY caJmd PLR

drf|l|vtravs

LlVsNAVS

L KYR-T KTRASAT P - VLVTPVIVAI S raqqgdtrIavrk

RTQHTGVLKllvTL

WVLAFLL-ygiap wvlaflIv - nIgBmI

TM III

TM IV

H1_HUMAN H2_HUMAN H3_HUMAN H4_HUMAN

Sec.Struct iHFMQQTlvRRBD - -

VT W

F

K

VM

T

A

I

I

N

F

Y

L

T

|L

M

- E V

Y

G

L V

D

G

L

V

T

F

Y

L

L

|l

M

NWY

F

L

I T

A

S

T

L

E

F

F

T

P

F

|s

V

EWY

I

L

A I

T

S

F

L

E

F

V

I

P

V

il

TM V

H1

HUMAN

A K

I^KA

V

RQHC

Q

H2

HUMAN

Y R

IIkv

A

RDQA

K

H3

HUMAN

L S

I YL N

I

QRRT

R

H4

HUMAN

M N

I Y W S

L

WKRD

I MAA

F

I L

C W

I

P Y

F

I

VMGA

F

I I

C W

F

P Y

F

T

I VS I

F

GL

C W

A

PY

T

L

L L G V

F

A V

CW

A

PY

S

TM VI

H1

HUMAN

F M

V I

A

F C KN C -

- C N E H

L

H M F T

I

WL

G

Y

I

N S

T

L

N P

L

H2_

HUMAN

F V

YR

G

LRGDDA

- I NEV

L

E A I V

L

WL

G

Y

A

N S

A

L

N P

I

H3_

HUMAN

M I

I R

A

ACHGHC

- VP D Y

W

YETS

F

WL

L

W

A

N S

A

V

N P

V

H4_

HUMAN

T I

VL

S

FYSSATGPKSV

W

Y R I A

F

|

Q

W

F

NS

F

V

lyaa|nrd lyplJhhs

LYPL jHKRl

R I L

H I

R

S---

QLF

Cc

R

L AN -

KL L

CP

Q

KL K -

K I F

CI

K

TM VII

H1_HUMAN --------------------------------------------------

H2_HUMAN R N sbkT S LRSNASQLSRTQSREPRQQEEKPLKLQVWSGTEVTAPQGATDR

H3_HUMAN I Q pHs SLEHCWK--------------------------------------

H4_HUMAN PSQHSRSVSS----------------------------------------

Sec.Struct -

Fig. 17.1 Amino acid sequence alignment of the four human HA receptors using ClustalX (Thompson et al. 1997) (see also ftp://ftp-igbmc.u-strasbg.fr/pub/ClustalX/). For ease of presentation, portions of the third intracellular loops (I3) have been omitted. The boxes indicate relative homologous protein domains, whereas the shaded areas indicate complete amino acid conservation between the subtypes. The asterisks indicate amino acid conservation with the rhodopsin sequence, whereas the filled triangles indicate the two Cys residues that are considered to form a disulphide bridge. Residues in bold have been mutated and studied for their functional role in receptor function (ligand binding, signalling, glycosylation, phosphorylation), as indicated in the tinyGRAP/GPCRDB database (Kristiansen et al. 1996) (see also http://tinyGRAP.uit.no/). Below the alignment the secondary structure prediction based on the homology with the rhodopsin structure is indicated (arrow = beta-sheet, cylinder = alpha-helix). The putative TM are indicated as well.

Table 17.1 Synopsis of histamine receptors

Hi

H2

H3

H4

Alternative names

none

none

none

none

Structural information (Accession no.) * = splice variants rep.

Human: 487 aa (P35367) Rat: 486 aa (NP_058714) Mouse: 488 aa (NP_03231 1)

Human: 359 aa (NP_071640) Rat: 3 58 aa (NP_037097) Mouse: 3 58 aa (NP_032312)

Human: 445 aa (Q9Y5N1)* Rat: 445 aa (Q9QYN8)* Mouse: 445 aa (P58406)

Human: 390 aa (Q9H3N8) Rat: 391 aa (AAK97381) Mouse: 391 aa (AAK97380)

Chromosomal location (Human)

3p25

5q35.3

20q13.33

18q11.2

Selective agonists

2-Thiazolylethylamine Histaprodifen

Dimaprit

Amthamine

Impromidine

R-a-Methylhistaminea

Imetita

(Histaminea Immepipa)

Selective antagonists

Pyrilamine (i.e. Mepyramine) d-Chlorpheniramine

Ranitidine Famotidine

Iodoaminopotentidine Zolantidine

Thioperamidea

Clobenpropit

(Thioperamidea)

Radioligands

3H-Pyrilamine 11 C-Doxepin

3 H-Tiotidine

125I-Iodoaminopotentidine

3H-R-a-methylhistamine 3H-Na-methylhistamine 125I-Iodophenpropit 125I-Iodoproxyfan

3H-Histamine 3H-Na-methylhistamina

G protein coupling Expression profile

Gai/o

Gai/o

Heart, smooth muscle, CNS, endothelium, adrenal medulla, sensory neurones

Gastric mucosa, T-lymphocytes, mast cells, basophils, CNS

Eosinophils, basophils

Physiological function

Endothelium-derived vasodilation; increased vascular permeability; intestinal and smooth muscle contraction; CNS wakefulness; decreased appetite; CNS depolarization

Gastric secrection; increased chronotropic and inotropic effects; CNS inhib of voltage-and calcium-activated K channels

Inhibition of release of several transmitters; increased sleep; decreased food and water intake

Possible immunomodulation

Knockout phenotype Impaired locomotor and Gastric hypertropy and Unknown Unknown exploratory behaviour; hypergastrinemia; increased defective leptin (feeding) and T-helper cell cytokine release orexin A (arousal) responses; decreased nociception, increased IgE antibody responses

Disease association Alzheimer's, epilepsy, Gastric acid disorders, migraine ADHD, Alzheimer's, epilepsy, Unknown narcolepsy, obesity obesity

A summary of the main features of the four known histamine GPCRs is shown. aMany 'selective' H3 agonists and H3 antagonists also have appreciable activity at H4 receptors.

encoding of the H2 receptor, which is intronless (Gantz et al. 1991b). The sequences from various species show considerable homology (80-90 per cent) and encode for a receptor protein of 359 (dog, man, and guinea-pig) or 358 (rat and mouse) amino acids, with an apparent molecular weight of approximately 40 kDa. The human receptor is located on chromosome 5. Since a consensus sequence for N-linked glycosylation is present in the N-terminal extracellular tail, the actual molecular weight of the receptor is significantly higher. Currently, a growing body of evidence suggests that GPCR dimers can be formed and may play an important role in receptor function. Interestingly, H2-receptor oligomers have been observed in Sf9 cells (Beukers et al. 1997; Fukushima et al. 1997), although the significance of this finding remains uncertain.

With respect to receptor recognition, the H2 receptor (like the H1) uses the highly conserved aspartate residue in TM3 (Fig. 17.1) for the binding of HA and H2-receptor antagonists (Gantz etal. 1992). Furthermore, mutagenesis studies indicate that the Thr and Asp residues in TM5 of the H2 receptor are likely to interact with HA and the antagonist [3H]tiotidine. More details on the ligand binding site of the human H2 receptor are currently not available.

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