Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 18 Pituitary Function
Pig SRGPLRPLCRPINATLAAENEACPVCITFTTSICAGYCPSMVRVLPAALPPVPQPVCTYR 60
Dog -------------------------------T---------------------------H
Mouse -----------V---------F--------------------------------------
Rat -----------V---------F--------------------------------------
Cattle ---------Q---------K---------------------K----VI---M--R----H
Goat ---------Q---------K---------------------K----VI---M--R----H
Sheep ---------Q---------K---------------------K----VI---M--R----H
Horse -------------------K----I-------------------M-----AI--------
Cat --E-----------------------V----T---------M------------------
Human --E----W-H----I--V-K-G------VN-T-------T-M---Q-V---L--V-----
** **** * * ** ** * * ** * * * ******* * ** ** ** ****
Pig ELSFASIRLPGCPPGVDPTVSFPVALSCHCGPCRLSSSDCGGPRAQPLACDRPLLPGLLFL 121
Dog --H---------------M---------R-------N---------S--------------
Mouse --R---V-----------I---------R---------------T--M---L-H-----L-
Rat --R---V-----------I---------R---------------T--MT--L-H-----LF
Cattle --R---V-----------M------------------T------T------H-P--DI---
Goat --R---V-----------M------------------T------T------H-P--DI---
Sheep --R---V-----------M------------------T------T------H-P--DI---
Horse --R---------------M--------------QIKTT---VF-D-----APQASSSSKDP 1
Cat --R---V-----------V---------R------------------------P-------
Human DVR-E--------R----V---------R-----R-T------KDH—-T--H-Q-S-----
* * ****** **** ********* **** ***
1 C-terminal extension in the horse:PSQPLTSTSTPTPGASRRSSHPLPIKTS
FIGURE 18-9 Sequence comparison of the β -subunit of LH. See the legend for Figure 18-6 .
Rat
Mouse
Dog
Pig
Cattle
Goat
Sheep
Horse
Cat
Human
3 . LH and FSH
Luteinizing hormone (LH), which is identical to the interstitialcell-stimulating
hormone, and follicle-stimulating hormone
(FSH) are produced by the gonadotropic cells of the AL.
a . Gene Expression
In the gonadotropes α GSU appears to be the lead protein
before the expression of the β -subunits, which determine the
hormone specificity ( Pope et al. , 2006 ). Next the β -subunits
arise in the bihormonal gonadotropes. During development
of the pituitary, transcription factors Pitx, Hesx1, Lhx3,
SF-1, and Otx1 regulate gonadotropin subunit expression
( Brown and McNeilly, 1999 ). Although LH and FSH are
produced within the same gonadotrope, its gene expression
and secretion pattern are different.
In primates, multiple copies of LH β -related genes have
been identified, the chorionic gonadotropins (CG), which
are expressed in the placenta for the maintenance of early
pregnancy. Apart from primates, only in equids has this
placental production of CG been well described ( Jorgensen
et al. , 2004 ). In the horse, placental eCG β is derived from
the same gene that encodes pituitary LH β ( Saneyoshi et al. ,
2001 ). For pituitary LH β expression, three highly conserved
response elements have been found in the promoter
region that bind the early growth response protein (Egr-1),
the orphan nuclear factor SF-1, and the homeodomain protein
Pitx1 ( Jorgensen et al. , 2004 ; Melamed et al. , 2006 ).
For the regulation of basal FSH β gene expression Lhx3
plays a prominent role, whereas a direct effect of SF-1 on
FSH β expression is not demonstrated in the ovine pituitary
gland ( Baratta et al. , 2003 ).
The LHβ promoter is sensitive to stimulation by GnRH
via Egr-1 and inhibition by androgens. The activated androgen
receptor (AR) binds SF-1 to block communication via
Pitx1 ( Jorgensen et al. , 2004 ). The AR, however, increases
FSH β gene promoter activity, as also documented for the
progesterone receptor (PR) and glucocorticoid receptor
(GR) ( Thackray et al. , 2006 ). Estrogens activate the LH β
promoter ( Melamed et al. , 2006 ). Inhibin, activin, and
follistatin, originally found as hormones from the gonads
but they may also be produced within the pituitary, are
important regulators of LH and FSH synthesis and release.
Activin stimulates FSH β gene expression and mRNA stability,
whereas inhibin and follistatin inhibit FSH β gene
expression and accelerate the degradation of FSH β mRNA
( Gregory and Kaiser, 2004 ). As activin stimulates and
inhibin inhibits expression of GnRH receptors, an indirect
effect on LH β expression and release also can be found.
b . (Pro)hormone
After cleavage of the signal peptide, LH β proteins are
formed of 121 amino acids ( Fig. 18-9 ). Exception is the
horse sequence, which shows a highly variant C-terminal
part that is also some 14 to 28 amino acids longer. The β -
subunit contains six intrachain disulfide bridges. In humans,
LH β has one unique N-linked glycosylation at asparagine 30.
In the horse, asparagine 13 is glycosylated and in addition
12 O-glycosylation sites have been found ( Bousfield et al. ,
2001 ). The percentage glycosylation is related to increased
plasma half-life and thus bioavailability of the hormones.
The FSHβ chain consists of 111 amino acids, six intrachain
disulfide bridges, and two N-linked glycosylation sites
at asparagine 7 and 24. The N-linked oligosaccharide chains
are critical for bioactivity. Deglycosylated FSH may act as a
potent FSH antagonist ( Fares, 2006 ). The sequence of canine
FSH shows the lowest homology (approximately 80%) with
the sequences of other species ( Fig. 18-10 ), which may cause
limitations to the use of heterologous immunoassays for
proper FSH measurements in the dog.