1
PHYL 423
GASTROINTESTINAL ENDOCRINOLOGY
THE ENDOCRINE SYSTEM,
HORMONES AND ENDOCRINOLOGY
Classically ‘Endocrinology’ has been defined as ‘the
branch of science concerned with endocrine glands
and their secretions.’ These secretions are called
hormones. The concept of endocrinology has its
origins in a discovery made in 1902 by William
Maddox Bayliss and Ernest Henry Starling. They
showed that acidification of the upper intestine
resulted in secretion of pancreatic juice. It was
subsequently demonstrated that a substance in
duodenal mucosal extracts stimulated pancreatic
bicarbonate secretion in both innervated and
denervated pancreases. They called the substance
‘secretin’. In 1905, Starling introduced the word
‘hormone’ a term derived from the Greek meaning
‘to arouse’ or ‘to excite’. In the same year, gastrin
was identified by John Edkins.
Several important developments have made it
necessary to expand the field of endocrinology and
the definition of ‘hormone’, of which two will be
discussed here. Firstly, not all hormones are produced
by distinct isolated glands, and this is particularly
relevant to Gastrointestinal Endocrinology, because
the GI hormones are located in a Diffuse Endocrine
System. Secondly, under Starling’s original
definition a ‘classical’ hormone was considered to be
‘a signalling molecule that is secreted in small
amounts into the blood, in which it is carried to its
target organs’. This definition has had to be expanded
to include molecules that are neither secreted into,
nor transported by, the bloodstream.
MODERN CONCEPTS REGARDING
HORMONES
The discovery, that hormones can be secreted into the
interstitial space and act on neighbouring cells, led to
a rethinking of the hormone concept. An appropriate
definition of hormones, which is general enough to
include most of their different modes of secretion and
action, is that they are: Intercellular messengers
that act on specific receptors and are effective at
micromolar concentrations or less. Under this
definition hormones can be classified according to
four chemical classes.
CHEMICAL CLASSES OF
HORMONES
1. Peptides and Proteins
The most abundant hormones are peptides or proteins
consisting of variable numbers of amino acids. The
gastrointestinal tract produces a wide range of
peptide hormones, the structures of two examples of
which are shown in Fig. 1.
HUMAN GLUCOSE-DEPENDENT
IINSULINOTROPIC POLYPEPTIDE
(GIP)
1
1
Y
HUMAN GLUCAGON-LIKE
PEPTIDE-1
(GLP-1)
A
E
G
T
F
I
S
D
H
A
E G
T
F
T
S
V
S
S
S
I
D
Q
Q
F
H
I
K
D
M
A
E
K
A
F
18
A
Q
G
E
L
Y
18
I
V
N
W
D
Y
A
30
L
L
A
Q
K
G
K
K
W
30
L
V
K
G
R
34 N
D
Q
W
40
42
T
I
N
H
K
Figure 1. Structures of the GI Peptide
Hormones GIP and GLP-1
2. Derivatives of Amino Acids (Amines)
Modified amino acids are also utilized as hormones
(Fig. 2). Examples of these are derivatives of tyrosine
(adrenaline, thyroid hormones), histidine (histamine),
and tryptophan (serotonin; 5-hydroxytryptamine).
Adrenaline
(Epinephrine)
Histamine
Thyroxine
Serotonin
Figure 2. Examples of Hormones that are
Derived from Amino Acids
2
inflammatory actions and suppresses tumor growth.
Adrenaline is not strictly a GI hormone since its
major site of synthesis is the adrenal. However it is
important in the regulation of GI blood flow during
stress. Thyroid hormones (Thyroxine (T4);
Triiodothyronine (T3)) are produced by the thyroid.
However the GI tract both acts as a reservoir for
thyroid hormone storage and, as in other tissues,
actively converts T4 to the major active form, T3.
The major role of thyroid hormones in the gut is
probably regulation of cell metabolism.
Histamine is a central molecule in the regulation of
acid secretion and serotonin is involved in the
regulation of gastrointestinal motility and secretion.
Figure 4. Structure of a Prostaglandin and
Platelet Activating Factor
3. Steroids
Steroids are derived from cholesterol. A number of
steroids have defined actions on the gastrointestinal
tract. For example, progesterone and estradiol
modulate GI motility and cortisol influences GI tract
development, Aldosterone is involved in the
regulation of ion and water transport.
Progesterone
Estradiol
Until recently, nutrients were excluded from the
definition of hormone. However, 'orphan' G ProteinCoupled Receptors (GPCRs) that bind fatty acids
have now been identified (Fig. 5) in the intestine
(enteroendocrine cells
& mast cells) and in
pancreatic islets (beta cells). These receptors are
coded for in a gene cluster and exhibit different
responsiveness to fatty acids of different chain
length.
Human Chromosome 19q13.1
CD22
Glucocorticoids
Cortisol
GPR40
GPR41
GPR42
Aldosterone
Receptor
Figure 3. Examples of Steroids With
Gastrointestinal Functions
Although most steroids are synthesized outside of the
GI tract, the liver and intestine contain high
concentrations of several isoforms of the enzyme 17
-hydroxysteroid dehydrogenase and they are
probably major sites of inactivation of steroids.
4. Fatty Acids
The major fatty acid derivatives are members of the
eicosenoid family, which includes the prostaglandins,
leukotrienes, thromboxanes, and prostacyclin, and
platelet-activating factor (Fig. 4), which is a
phosphatidylcholine-like molecule. Various members
of the prostaglandin family have been shown to
regulate GI secretion and motility, and to have
protective effects on the GI mucosa. PAF has anti-
Specificity
GPR40 Medium to Long
Chain FAs
GPR41 Short Chain FAs
GPR43 Short Chain FAs
Figure 5. The GPR40-43 Family
GPR43
3
synthesized in cells that are distributed diffusely
throughout the stomach and intestines.
When hormones, such as oxytocin and vasopressin,
are secreted by neurons into the bloodstream, the
mode of signal transmission is referred to as
neuroendocrine secretion. It is not thought to be a
normal mode of transmission by GI hormones.
HORMONE-TARGET
RELATIONSHIPS IN THE
GASTROINTESTINAL TRACT
The following terms have been introduced into the
literature to describe the manner in which the various
hormones act on their target tissues. Examples that
are of relevance to the functioning of the
gastrointestinal tract will be considered.
C. Paracrine
In paracrine secretion the hormone (parahormone)
is released into the extracellular space and diffuses to
neighbouring cells within a fixed area of influence
(Fig. 6C). Some of these locally acting
parahormones, for example somatostatin, may
additionally act in an endocrine manner. Some texts
also refer to neurotransmission (release of
transmitters from neurons) as paracrine secretion.
A. Endocrine and B. Neuroendocrine
This refers to the ‘classical’ secretion of a messenger
into, and transport by, the bloodstream (Figs. 6A and
6B). Outside of the GI tract, many hormones are
synthesized in discrete glands, growth hormone in the
pituitary and insulin in the endocrine pancreas (islets
of Langerhans) for example, but the GI hormones are
A. ENDOCRINE
(E.G. INSULIN)
A.
ENDOCRINE
(E.G. INSULIN)
Secretory Granule
...... .
...... .........
Hormone
...
..
. ... . . . . .
.
. .
..
...
. .
Receptors
B. NEUROENDOCRINE
OXYTOCIN)
B.(E.G.
NEUROENDOCRINE
(E.G. OXYTOCIN)
C. PARACRINE
(E.G. SOMATOSTATIN)
D. AUTOCRINE
(E.G. GROWTH FACTORS)
........ ..
.
........ ... .....
.....
..
.. . .
........ ..
.
........ .... .....
. ..
.
.
. . .. .
E. JUXTACRINE
(E.G. EGF)
F. INTRACRINE
(E.G. STEROID HORMONES
T4/T3)
.
..
.
G. EXOCRINE (E.G. EGF)
Figure 6. Hormone-Target Relationships
. .
.
.
.
.
..
. ..
4
D. Autocrine
As with paracrine secretion, the hormone is secreted
into the extracellular space, but in this case it acts on
its cell of origin (Fig. 6D). Many growth factors act
in this way, and their overproduction can lead to
tumor development.
Examples of GI hormones signaling by endocrine,
paracrine and autocrine pathways are shown in Table
1.
Mode of
Communication
Endocrine
Paracrine
Autocrine
Type of
Regulator
Hormone
Parahormone
Autocrine
Example
Secretin
Somatostatin
IGF-1
Table 1. Examples of Hormones
E. Juxtacrine
In some cases the hormone is synthesized as a
membrane bound precursor molecule. This may be
cleaved to produce a soluble molecule or remain
attached to the plasma membrane where it can
influence neighbouring cells. When it remains
attached, its mode of action is termed juxtacrine (Fig.
6E). One example is epidermal growth factor (EGF).
F. Intracrine
Some hormones are synthesized within the cells in
which they act. For example, steroid hormones can
be produced by their target cells and thyroxine (T4) is
secreted by the thyroid gland but metabolized to the
more active form, triiodothyronine (T3) by
intracellular enzymes in cells in the periphery,
including the GI tract. This form of signal
transmission is termed intracrine (Fig. 6F).
G. Exocrine
A few signalling molecules are secreted into the
lumen of a gland and are resistant to proteolytic
enzymes which are also secreted. EGF, for example,
is produced by the salivary glands and can act within
the stomach. The Trefoil Peptides and the
antibacterial defensins are components of the innate
immune system.
H. Pheromones
Chemicals released by an organism into the
environment that alter the behaviour or gene
expression of another organism of the same species
are referred to as pheromones. They have been
extensively studied in lower species, such as insects,
where they act as sex attractants, and they probably
serve a similar role in humans. Many mammals have
anal glands that secrete pheromones.
THE DIFFUSE ENDOCRINE SYSTEM
AND ENTEROENDOCRINE CELLS
The term APUD (Amine Precursor Uptake and
Decarboxylation) cells was originally introduced to
describe cells exhibiting co-localization of
biologically active peptides with specific amines and
their synthesizing and processing enzymes. It is now
more common to call them enteroendocrine cells.
They are distributed throughout the GI tract, hence
the combined system is termed the Diffuse
Endocrine System. Although the cells are scattered
in the gut mucosa, where they represent
approximately 1% of the epithelial cell population,
they constitute one of the largest populations of
hormone-producing cells in the body. Some of the
enteroendocrine cells are of an open type with
microvilli that sense changes in the GI lumen,
whereas others only receive information from the
bloodstream or neighbouring cells and are called
closed cells.
During embryological development of the GI tract,
the enteroendocrine cells have the same origin as
absorptive and exocrine secretory cells: progenitor
cells in the endodermal epithelium. In the mature
intestine, self-regenerative pluripotent stem cells in
the crypts differentiate into one of the four lineages
of mature epithelial cells: enteroendocrine, goblet,
paneth or absorptive (Fig. 7). Differentiation is
regulated by specific transcription factors. For
example, specific transcription factors, including
MATH1 and Neurogenin 3 are necessary for
commitment of a Gut Progenitor Cell to the
Endocrine Lineage. The presence of other
transcription factors is required for terminal
differentiation to produce a cell type expressing a
specific hormone. For example, Paired Box Protein
4/6 (Pax4/6) is one factor involved in differentiation
into GIP cells.
THE
GASTROINTESTINAL HORMONES
A large number of biologically active peptides have
been identified in the GI tract. For the current
overview,
peptides
acting
primarily
as
neurotransmitters
(neuropeptides),
chemokines
produced by the immune system and the majority of
growth factors will not be considered further. The
major hormones and paracrine-acting substances
produced, and acting, in the GI tract are presented in
Table 2. (Note that Tables 2-4) are for reference).
5
Figure 7. Scheme of the Developmental Pathways of Intestinal Cells (Modified from Fujita et al
Pediatric Diabetes. 5 Suppl 2:57-69, 2004)
6
HORMONE
Cholecystokinin
CELL
TYPE
CCK
GIP
K
Gastrin
G
Ghrelin
GLP-1

L
GLP-2
Histamine
Motilin
Neurotensin
Oxyntomodulin
Peptide YY
Secretin
L
ECL
Mo
N
L
L
S
Serotonin (5-HT)
Somatostatin
EC
D
MAJOR ACTIONS
Stimulation of exocrine pancreatic secretion (protein) and
gallbladder contraction; relaxation of Sphincter of Oddi; Satiety
Stimulation of insulin biosynthesis and secretion, pancreatic cell mitogenesis and survival; inhibition of acid secretion (?)
Stimulation of gastric acid and pepsinogen secretion;
Stimulation of pancreatic and gastric mucosal growth
Stimulation of food intake
Stimulation of insulin biosynthesis and secretion, pancreatic cell mitogenesis and survival; inhibition of glucagon secretion;
inhibition of gastric emptying; suppression of food intake
Regulation of gastrointestinal growth
Stimulation of acid secretion
Regulation of the Migrating Myoelectric Complex
Regulation of motility
Regulation of motility (?); Satiation
Gastric Secretion (?); Satiation
Stimulation of exocrine pancreatic & hepatic secretion (HCO 3/Water),
Regulation of motility
Inhibition of exocrine and endocrine secretion and motility
Table 2. Major Hormones and Paracrines of the Gastrointestinal Tract (Note that growth factors (e.g.
IGF-I, TGF-) and neurotransmitters (e.g. NPY, enkephalins, tachykinins) are not included. GIP =
Gastric Inhibitory Polypeptide or Glucose-dependent Insulinotropic Polypeptide; GLP-1 = Glucagon-like peptide-1
7
HORMONE FAMILIES
A multitude of bioactive peptides have been
discovered, many of which do not have clearly
identified functions. Some ‘hormones’ are produced
by neurons, in addition to endocrine/paracrine cells.
From sequencing and structural studies it has been
demonstrated that some hormones can be classified
into families, based on homology (Table 4). This can
be based on either overall primary structure or
regional homology.
1. Overall Primary Structure
The PP-fold family of peptides displays sequence
similarities of 45-70%. They share a very similar
tertiary structure because of homologous residues
that are important for stabilization of the 3dimensional fold structure.
The main homology within the gastrin family is
located in the C-terminal tetrapeptide –Trp-Met-AspPhe-NH2. This region of the molecule is also crucial
for biological activity; modification of any residue
severely reduces receptor binding and biological
activity. There is little similarity in either mRNA or
peptide amino acid sequences outside of the common
site and immediately adjacent region.
Homology among GI peptide hormones, peptide
neurotransmitters and growth factors is assumed to
reflect their phylogenetic evolution by gene
duplication and subsequent mutation (Fig. 9). In
some cases there is evidence for a single common
ancestor of several peptides with vastly different
functions. Receptors of hormones in these families
also share regional homology.
2. Regional Homology
The major homology of the secretin family resides in
the N-terminus (Fig. 8), a region that is critical for
biological activity. Removal of the N-terminal 2
amino acids by the enzyme dipeptidyl peptidase IV
results in loss, or a significant reduction in, biological
activity of these peptides.
Secretin Family
Gastrin Family
Secretin
Gastrin
Glucagon
CCK
GLP-1
Cerulein+
GLP-2
Cionin+
GIP
VIP
PHI
GHRH
PACAP
Insulin Family
Insulin
IGF-I
IGF-II
Relaxin
PP-fold Family
PP
PYY
NPY
Figure 8. Amino acid sequences
of the Secretin family
Somatostatin Family
Somatostatin
Corticostatin
Motilin Family
Motilin
Ghrelin
Table 4. Gastroenteropancreatic Peptide
Families
VIP = Vasoactive Intestinal Polypeptide; PHI = Peptide
Histidine Isoleucine; GHRH = Growth Hormone Releasing
Hormone; PACAP = Pituitary Adenylyl Cyclase-Activating
Peptide; IGF-I = Insulin-Like Growth Factor-I; PP =
Pancreatic Polypeptide; PYY = Peptide YY; NPY =
+ Not found in mammals
Neuropeptide YY
Figure 9. Evolution of the Growth
Hormone Releasing Hormone Superfamily
8
GASTROINTESTINAL
PEPTIDE HORMONE
BIOSYNTHESIS AND SECRETION
Introduction
As in other cell types, protein synthesis in hormone
secreting cells begins with mRNA synthesis in the
nucleus and its passage into the cytoplasm.
Translation takes place on the ribosomes. The peptide
hormone precursor is delivered into the lumen of the
rough endoplasmic reticulum, from whence it is
transported in transitional vesicles to the Golgi
apparatus (Fig. 10). During transport through the cis
and trans Golgi, and trans Golgi network (TGN), the
hormone precursor is processed and modified in a
cell specific manner. Movement between the
compartments occurs by budding and fusion of
transporting vesicles.
Figure 10. Generalized Diagram of the Synthesis and Transport of Protein/Peptide Hormones
(Boron, WF & Boulpaep, EL
Medical Physiology, 2012)
9
Gene Structure
The upstream (5') end of peptide/protein hormone genes generally contains promoter/enhancer regions for regulation
of gene transcription. The structural gene consists of variable numbers of introns and exons (Fig. 11)
EXON
PROMOTER
EXON
INTRON
EXON
INTRON
INTRON
GENE
Post-Transcriptional
Modification
Methyl-G
AAAAAAAAA
Translation
Preprohormone
Post-Translational
Modification
Hormone
Figure 11. Outline of Events Involved in the Biosynthesis of a Peptide Hormone.
The gene consists of a promoter region and varying numbers of introns and exons. The primary RNA transcript, produced
through the action of RNA polymerase, is processed by removal of the introns, followed by capping with 7-methyl guanosine (7Methyl-G) at the 5’ end and addition of a poly-A tail at the 3’ end. Translation on the ribosome results in a peptide precursor, the
preprohormone with an N-terminal signal peptide. This is processed to produce mature hormone.
10
Preprohormone Biosynthesis and Processing
For the majority of hormones the mRNA codes for a precursor that is considerably longer than the secreted peptide
(Fig. 11). This preprohormone contains a signal peptide that is important for directing the peptide chain into the
cisternum of the endoplasmic reticulum, where the signal peptide is cleaved off by a peptidase. The prohormone is
processed further into the hormone by specific enzymes, that include prohormone convertases (Fig. 12),
Preprohormone!
Removal of Pre-Peptide
Propeptide
Cleavage
Single Peptide
e.g. Motilin, GIP
Prohormone!
Multiple Peptides
e.g. Proglucagon
Figure 12. Prohormone Processing Can Result in the Formation of Single or Multiple
Hormones
Post-Translational Modifications
A number of hormone-specific post-translational
modifications can occur, including addition of
sulphate groups to tyrosine residues.
11
Multiple Hormone Products from a
Single Gene
2. Multiple Hormone Products from a Single
With many hormone genes, such as that coding for
prepromotilin (Fig. 12) there is a single, biologically
active hormone produced from the precursor.
However, a hormone gene can give rise to more than
one hormonal product.
There are several examples of prohormones that give
rise to more than one biologically active hormone as
a result of processing by peptide convertase enzymes.
Proglucagon for example is processed to produce
mainly GLP-1 and GLP-2 in the intestine and brain
neurons, but mainly glucagon in the -cells of the
pancreas.
Prohormone
1. Multiple Products of a Prohormone with a
Single Active Sequence
3. Alternative splicing of RNA transcripts
Members of the gastrin family, for example
cholecystokinin (Fig. 13), are examples of peptides
produced by a single gene that encodes one
prohormone from which peptides of different length
are cleaved, all of which contain the biologically
active region of a single hormone. ProCCK is
processed into numerous multiple forms (Fig. 13)
whereas Gastrin-17, -34 and-71 are formed from
progastrin. Somatostatin-14 and -28 are produced
from prosomatostatin, The significance of such
complexity is not understood.
Following production of the primary RNA transcript,
it can sometimes be processed in more than one way,
to produce mRNA transcripts that code for alternative
peptide products. Examples of this include the
secretin gene (Fig. 14) and the gene coding for
calcitonin and calcitonin-gene related peptide
(CGRP).
In the case of secretin, the precursor RNA is
processed to produce two mRNA transcripts, one of
which codes for a peptide that is processed to form
secretin-27 and the other codes for secretin-71.
Although different functions for the two peptides
have not been established, the larger form exhibits a
longer half-life in plasma.
Preprohormone Gene!
Alternative
mRNA Splicing
Secretin-27
Figure 13.
Alternative Processing of CCK Produces
Multiple Products of Different Length
Containing the Same C-terminal
Biologically Active Region
Secretin-71
Figure 14. Alternative mRNA Splicing
Results in the Production of Secretin-27
and Secretin-71
12
SECRETION OF
GASTROINTESTINAL PEPTIDE
HORMONES
There are two major pathways by which hormones
are secreted in an endocrine or paracrine manner:
constitutive and regulated (Fig. 10). Secretory
vesicles bud-off from the trans-Golgi network. Small
amounts of hormone are transported to the plasma
membrane in such vesicles continuously, and in a
non-regulated manner. Release of the vesicle
contents, which occurs by exocytosis, is termed
constitutive secretion. The major pool of peptide
hormone is stored until required in secretory
granules, which mature from budding vesicles. A
specific stimulus to the cell results in fusion of
granules with the plasma membrane and release of
their contents into the extracellular space.
The stimuli that result in secretion are cell type
specific. Glucose and GI incretin peptides (GIP,
GLP-1) stimulate release of insulin from the -cell.
With continuous stimulation granules situated at a
distance from the site of release will move along
microtubules/microfilaments
to
the
plasma
membrane.
The overall process is termed stimulus-secretion
coupling and this type of secretion is referred to as
regulated. Granules are recycled. Following
exocytosis
hormones
either
pass
through
fenestrations (windows) in the capillaries into the
bloodstream or act via alternative pathways (e.g.
paracrine or autocrine) as described earlier.
The secretion of gastrointestinal hormones varies
according to the time of day and the frequency and
duration of feeding.
Figure 15. Histamine Secreted by
Enterochromaffin-Like Cells Maintains Basal
Gastric Acid Secretion
2. Stimulated Secretion Prior to Food Intake
Recent studies indicate that plasma levels of the
gastric hormone ghrelin increase progressively
during fasting and fall to a nadir within ~1hr. after
eating (Fig. 16). Ghrelin has been shown to influence
hypothalamic neurons involved in regulating food
intake, and evidence is accumulating supporting a
role as a trigger for feeding.
1. Basal Secretion
It is believed that most, if not all, enteroendocrine
cells secrete small amounts of hormone between
meals. It is not clear as to whether this ‘basal
secretion’ is constitutive or regulated, but in some
cases it serves a well-defined function. Secretion of
histamine from gastric ECL cells, for example (Fig.
15), is believed to be relatively continuous and to be
responsible for maintaining a basal level of acid
secretion through paracrine action on parietal cells. In
response to feeding, secretion is then potentiated by a
number of factors (Fig. 15).
Figure 16. Representation of the Relationship
Between Ghrelin Secretion and Hunger
Several hormones are released prior to food intake as
a result of neural signals originating in the brain. This
‘cephalic’ or ‘psychic’ phase of secretion is
exhibited by gastrin and CCK.
13
3. Secretion During a Meal
Secretion of most GI hormones is stimulated during a
meal. Numerous factors can impact on the hormonesecreting cells, including the enteric nervous,
endocrine and immune systems (Fig. 17). Some of
the endocrine cells also sense the luminal
environment and respond to changes in pH or
nutrients. The overall secretion rate of a hormone will
be determined by the integrated responsiveness to the
various stimuli.
HCO3-
PANCREATIC
DUCT CELL!
SECRETIN
Enteric
Nerves
Endocrine
System
Immune
System
SECRETIN
CELL
!
H+
LUMEN
!
DUODENAL
MUCOSA
Figure 18. Secretin Secretion in Response to
Reduced Intraduodenal pH
Nutrients
Figure 17. Major Factors Involved in the
Regulation of GI Hormone Secretion
The specific pathways involved in regulating
secretion of the majority of the GI hormones will be
discussed later.
The secretin, or S-, cell is an example of an open
endocrine cell (Fig. 18) that releases its hormone into
the bloodstream in response to acid in the lumen of
the duodenum. One target organ is the pancreas
where it stimulates fluid secretion from duct cells.
In contrast, somatostatin and histamine act in a
paracrine manner in the stomach: somatostatin
inhibiting (Fig. 19) and histamine stimulating acid
secretion from parietal cells. Somatostatin can also
act in an autocrine manner.
Figure 19. Paracrine and Autocrine Actions of
Somatostatin
14
4. Interdigestive Secretion of Hormones
During the interdigestive period, residual material
from previous meals remains in the intestine. Motilin
is secreted from the gut (Fig. 20) and appears to
modulate the migrating myoelectric complex (MMC)
that is responsible of moving the residue down the
intestine. It is unclear as to the initiating factor
responsible for stimulating motilin, or whether the
MMC is a stimulus.
Figure 20. Motilin Secretion and the Migrating
Myoelectric Complex (MMC) (Physiology 4th
Edition. Berne, RM & Levy, MN. Mosby 1998)
15
ACTIONS OF
GASTROINTESTINAL HORMONES
The various actions of GI hormones will be discussed
in later sessions, but it is important to realize that
their actions are mediated via specific receptors and
signal transduction systems. These receptors may be
situated on the cell surface or intracellularly.
Molecules acting via cell surface receptors, including
peptides, proteins, and small charged molecules such
as adrenaline and histamine, are fairly hydrophilic
and cannot therefore cross the plasma membrane.
Interaction with a cell surface receptor triggers the
production of intracellular molecules referred to as
second messengers. Intracellular receptors for
steroids and the thyroid hormones act as transcription
factors and influence gene expression.
peptides have binding sites within the transcellular
domains.
Hormone binding results in activation of a G protein
exchange of GTP for GDP and dissociation of from
 subunits, both of which can be involved in
modulating intracellular enzyme activities. This leads
to the increase, or decrease, in levels of one or more
of several second messengers, including:
1. Cyclic Nucleotides, e.g. Cyclic AMP (Figure 22)
2. Inositol Phosphates and Diacylglycerol (Figure 23)
3. Ca2+ and Calmodulin
Figure 22. Receptor-G Protein Mediated
Activation of Adenylyl Cyclase
CLASSES OF CELL-SURFACE
RECEPTORS
1.
G
Protein-Coupled
Seven
Transmembrane-Spanning
(Heptahelical)
Receptors
Hormone
²#
PEPTIDE
HORMONE
TM HELICES
! s!
GTP
#
GTP
P
EXTRACELLULAR SIDE
! s!
GDP!
The G protein coupled receptors consist of a single
polypeptide chain that crosses the membrane seven
times. The membrane-spanning regions are helical
(heptahelical) (Fig. 21).
NH2
Adenylyl
Cyclase
Receptor
ATP
cAMP ( ) ATP
GDP
C
C
C
C
R
R
PKA
Protein
Phosphorylation
Figure 23. Receptor-G Protein Mediated
Activation of Phospholipase C
g
b
a
Hormone
CYTOSOLIC SIDE
PIP2
DAG
Receptor
COOH
²#
! q!
Figure 21. Diagram of a Prototypical G
Protein-Coupled Receptor
Ligand binding of larger polypeptide hormones
involves the extracellular N-terminal domain
andextracellular loops. Smaller peptides and non-
PLC
! q!
GDP!
IP3
PKC
GTP
#
GTP
GDP
P
Endoplasmic
reticulum
Ca2+
16
2.
Single
Receptors
Transmembrane
Spanning
Polypeptide chains constituting this class of receptors
only span the membrane once. Such receptors may
consist of a single (EGF) or multiple (insulin/IGF-I)
subunits (Fig. 24). However most of the single-chain
receptors, such as that for growth hormone, undergo
dimerization before or during hormone binding.
Growth Hormone
Insulin/IGF-I
Exterior
S
a
S
S
S
a
S
S
b
Tyrosine
Kinase
Domains
b
Cytosol
P
K
Kinase
P
K
K
Plasma
Membrane
P
K
Kinase
Figure 24. Representative Examples of Single
Transmembrane Spanning Receptors
Some of the single transmembrane spanning
receptors contain tyrosine kinase domains that are
activated on ligand binding (e.g. insulin, EGF)
whereas others activate tyrosine kinases bound to
specific regions in their intracellular domains.
Cascades of kinase phosphorylation can be activated.