Transcript PEPTIDE HORMONES

PEPTIDE HORMONES
& HORMONES THAT USE
CELL SURFACE
RECEPTORS
Endocrine mediators
OUTLINE:
1.
2.
3.
4.
5.
Sizes, origins and fate.
Occurance in blood: bound/unbound.
Listing of major examples.
Receptors and receptor binding.
Tour of a selected peptide hormone:
insulin.
6. Tour of a second peptide hormone:
Sizes, origins and fate:
Due to the force of custom, “peptide hormones” is
a collective name that has been applied to peptides,
polypeptides and proteins that all function as
hormones. The name “factor” has also been
given to some of these peptides and originates
from a time when their peptide/protein nature was
still unknown. In the endocrine system of hormones
originating from the brain, some of the smaller
peptides that exist are from the hypothalamus and
anterior and posterior pituitary (hypophysis).
SOME EXAMPLES OF SMALL PEPTIDES:
THYROID RELEASING HORMONE (TRH)
FROM THE HYPOTHALAMUS, A PEPTIDE OF ~360 daltons
TARGET: ANTERIOR PITUITARY (RELEASE OF TSH)
Glu-His-Pro-NH2
VASOPRESSIN
FROM THE POSTERIOR PITUITARY, A PEPTIDE OF ~1040 daltons
TARGET: KIDNEY & ARTERIOLES (INCREASES WATER REUPTAKE AND BLOOD PRESSURE)
OTHER PEPTIDE HORMONES FALL WITHIN
THE DEFINITION OF A PROTEIN (>10 kD).
SOME EXAMPLES:
GROWTH HORMONE
SOMATOTROPIN; 21.5 kD
FROM THE ANTERIOR PITUITARY;
TARGET: LIVER & BONE CAUSES
INCREASE IN METABOLISM &
BONE GROWTH.
THIS IS A PROTEIN THAT HAS
CONSIDERABLE a-HELICAL
AND RANDOM COIL STRUCTURE.
THE BLUE ARROWS INDICATE
APPROXIMATELY WHERE THE
HORMONE BINDS TO CELL
RECEPTORS.
PROLACTIN
22 kD WITH A STRUCTURE
SOMEWHAT SIMILAR TO
GROWTH HORMONE.
NOTE THE EXTENSIVE
a-HELICES. THE BINDING
SITES FOR THE RECEPTORS
ARE FROM THE LOWER SIDES.
AS SHOWN BY THE BLUE
ARROWS.
THIS HORMONE IS MADE IN
THE ANTERIOR PITUITARY TO
STIMULATE MILK PRODUCTION.
FATE OF PEPTIDE HORMONES
PEPTIDE HORMONES, AFTER BINDING TO
THEIR RECEPTORS, ARE COMMONLY TAKEN
UP BY THE CELLS THAT THEY BIND TO AND
TRANSPORTED TO LYSOSOMES WHERE THEY
ARE BROKEN DOWN .
THE LYSOSOME, IS AN INTRACELLULAR
SUBORGANELLE THAT CONTAINS SOME
30 DEGRADATIVE ENZYMES AS WELL AS AN
ACIDIC pH ENVIRONMENT THAT FAVORS
DESTRUCTION.
PEPTIDE HORMONES
IN THE BLOOD
THE ABILITY OF A HORMONE TO REACH ITS TARGET
TISSUE IS CRUCIAL. THE FOLLOWING IS KNOWN ABOUT
THAT TASK:
1. SMALL PEPTIDE HORMONES ARE AT A LOW
CONCENTRATION AND SOLUBLE ENOUGH TO BE
TRANSPORTED UNBOUND TO ANY SOLUBLE CARRIER.
2. LARGE “PEPTIDE” HORMONES, LIKE GROWTH
HORMONE, ARE CARRIED BY A SOLUBLE PROTEIN
WHICH IS SIMILAR TO THE PROTEIN RECEPTOR
IT BINDS TO ON CELL SURFACES.
IMPORTANT PEPTIDE HORMONES
(A SAMPLE LIST)
Not part of the hypothalamic “pecking order” of hormones.
“TOUR” OF A SELECTED PEPTIDE
HORMONE: INSULIN
INSULIN IS A POLYPEPTIDE
WITH A MW OF 5808. IT
ACTUALLY CONSISTS
OF 2 CHAINS JOINED BY
DISULFIDE BONDS (A CHAIN
= BLUE; B CHAIN = GREEN)
IF YOU STRETCH OUT THE
MOLECULE, YOU CAN SEE
THAT THER ARE 3 DISULFIDE
BONDS (1 INTRACHAIN ON
THE A CHAIN AND 2 INTERCHAIN BONDS)
SINCE ITS DISCOVERY IN 1921, INSULIN HAS BEEN
ONE OF THE MOST HEAVILY STUDIED HORMONES OF
ALL TIME. THIS IS DUE TO ITS ASSOCIATION WITH
DIABETES, A DISEASE IN WHICH GLUCOSE BOTH
STARVES SOME CELLS AND POISONS OTHER CELLS
WHILE IT DISORGANIZES ASSOCIATED METABOLIC
PATHWAYS.
THE ROLE OF INSULIN IS TO FACILITATE THE UPTAKE
OF GLUCOSE INTO CELLS BY MEANS OF GLUCOSE
TRANSPORT PROTEINS. THAT PROCESS IS CONTROLLED
BY TWO ASSOCIATED PEPTIDE HORMONES: GLUCAGON
AND SOMATOSTATIN – ALL PRODUCTS OF THE PANCREAS.
INSULIN IS PRODUCED
IN THE ISLET CELLS OF
THE PANCREAS (B CELLS)
GLUCAGON IS MADE IN
SOME DIFFERENT ISLET
CELLS CALLED A CELLS.
SOMATOSTATIN IS MADE
IN STILL OTHER ISLET
CELLS CALLED D CELLS.
THE ORGAN IS LOCATED
BEHIND THE SPLEEN &
ADJACENT TO THE SMALL
INTESTINE.
INSULIN IS INITIALLY FORMED AS A SINGLE POLYPEPTIDE
CALLED PREPROINSULIN. PROTEOLYTIC ENZYMES
REMOVE THE SIGNAL PEPTIDE. THEN DISULFIDE BOND
FORMATION TAKES PLACE TO FORM PROINSULIN.
IN THE LAST
STAGE, INSULIN
IS FORMED
WHEN
CONTINUED
LYSIS TAKES
AWAY THE
C PEPTIDE.
THE HORMONE
IS NOT ACTIVE
PREVIOUS TO
THIS STAGE.
BINDING OF INSULIN TO ITS RECEPTOR
PROTEIN
THE INSULIN RECEPTOR
PROTEIN IS A TETRAPEPTIDE COMPOSED OF
TWO ALPHA & TWO BETA
SUBUNITS. WHEN INSULIN
BINDS TO THE PROTEIN,
IT CAUSES A CONFORMATIONAL SHIFT THAT
ACTIVATES KINASE
ACTIVITY ON THE INSIDE OF THE MEMBRANE (ARROW).
THIS PRODUCES A SERIES OF PHOSPHORYLATIONS AS
A CASCADE OF MOLECULES (& FOLLOWING EVENTS). ONE
EVENT IS THE DELIVERY OF GLUT4 TO THE CELL SURFACE.
POST RECEPTOR ACTIVITY:
GLUT-4 SURFACE DELIVERY
SURFACE HORMONES THAT USE cAMP AS A
MEDIATOR
CORTICOTROPIN (ACTH) ***
DOPAMINE
EPINEPHRINE
FOLLICLE STIMULATING HORMONE (FSH) ***
GLUCAGON ***
LUTEINIZING HORMONE (LH) ***
MELANOCYTE STIMULATING HORMONE (MSH) ***
PARATHYROID HORMONE ***
PROSTAGLANDINS
SEROTONIN
SOMATOSTATIN ***
THYROID STIMULATING HORMONE (TSH) ***
*** peptides or polypeptides
GENERAL cAMP MECHANISM (stimulatory): THE KEY COMPONENTS ARE THE
HORMONE (b-EFFECTOR); RECEPTOR (in membrane); THE G PROTEIN;
ADENYLYL CYCLASE; AND cAMP.
(cascade starts here)
An example of a hormone and its receptor: THE THYROID STIMULATING
HORMONE AND THE TSHR PROTEIN
THE MODEL SHOWS THE OUTERMOST
PORTION OF THE RECEPTOR BOUND TO
THE HORMONE ON THE LEFT AT THE
LEUCINE RICH DOMAIN OF THE RECEPTOR.
AS WITH ALL HORMONE-RECEPTOR
BINDINGS, THE RECEPTOR WILL BE
INDUCED TO AFFECT A NEARBY G PROTEIN
PROBABLY IN THE VICINITY OF THE
C-TERMINAL END OF THE RECEPTOR.
IT IS CHARACTERISTIC OF THE HORMONE
TO INDUCE A CHANGE IN THE CONFORMATION
OF THE RECEPTOR THAT RESULTS IN SOME
ACTIVITY OF THE RECEPTOR SUCH AS –
ENZYME ACTIVATION OR PROTEIN BINDING.
WHEN A G PROTEIN IS AFFECTED, AT THIS POINT, THE G PROTEIN
“PICKS UP” THE MESSAGE INITIATED BY THE HORMONE. TYPICALLY GDP
(WHICH IS BOUND TO THE G PROTEIN) IS RELEASED AND REPLACED BY
GTP AS A NEW ASSOCIATION WITH THE TRANSFORMED RECEPTOR PROTEIN.
WHEN THIS OCCURS, THE
g AND b SUBUNITS DIFFUSE
AWAY FROM THE ORIGINAL
G PROTEIN.
AT 1, THE ACTIVATION
BEGINS. BY 3, THE
ACTIVATED PROTEIN
DIFFUSES TO ADENYLYL
CYCLASE TO ACTIVATE IT.
IN STEP 4, THE G PROTEIN
IS BACK TO ITS ORIGINAL
INACTIVE FORM.
G PROTEINS COME IN SEVERAL VARIETIES (= ISOFORMS) TO INACT
HORMONAL TRANSDUCTION MECHANISMS:
NOTES: GS = STIMULATORY G PROTEIN SINCE IT STIMULATES ADENYLYL
CYCLASE. GI = INHIBITORY G PROTEIN AS IT INHIBITS ADENYLYL CYCLASE.
NOTE THAT OTHER TYPES ARE FOUND IN SPECIALIZED TISSUES SUCH AS
BLOOD VESSELS, NOSE AND EYE.
AT THIS STAGE, GTP HAS BEEN FORMED AND HAS EITHER STIMULATED
OR INHIBITED ADENYLYL CYCLASE.
(cascade starts here)
cAMP may be broken down at this point BEFORE it enters into any
cascade. THIS IS ACCOMPLISHED WITH THE ENZYME cAMP PHOSPHODIESTERASE (PDE). HOWEVER, THE ENZYME CAN BE INHIBITED BY
METHYL XANTHINES SUCH AS CAFFEINE AND THEOBROMINE (FOUND
IN COFFEE, TEA, CHOCOLATE AND COLA DRINKS. THIS MAY RESULT,
FOR EXAMPLE, IN INCREASED GI MOTILITY
CASCADE MECHANISMS:
EXAMPLES OF THESE MECHANISMS
HAVE BEEN SEEN BEFORE. A WELLKNOWN ONE IS CONCERNED WITH
THE BREAKDOWN OF GLYCOGEN
INTO GLUCOSE WHEN THE
HORMONE IS EPINEPHRINE. THAT’S
SHOWN OFTEN SINCE MANY, MANY
OF THE OTHERS HAVE NOT BEEN
WORKED OUT WITH CERTAINTY –
THOUGH EVIDENCE FOR THEIR
EFFECTS ARE KNOWN.
NOTE: IN PARTICULAR, THE ENZYME
PROTEIN KINASE A (PKA) AND THE
OVERALL AMPLIFICATION FROM x
MOLECULES TO 10,000x MOLECULES
IN THE CASCADE.
PROTEIN KINASES EXIST AT THE START OF MANY CASCADES AND
EXIST IN A VARIETY OF ISOFORMS. THE ONE IN THIS CASCADE IS
PROTEIN KINASE A (PKA) WHERE “A” IS SHORT FOR: cAMP.
IN THE INACTIVE FORM
(BEGINNING OF THE
CASCADE), PKA HAS
FOUR SUBUNITS WITH
FOUR BINDING SITES
FOR cAMP. WHEN cAMP
BINDS TO THE SITES IT
CAUSES THE C (OR
CATALYTIC) SUBUNITS
TO DISSOCIATE FROM
THE R SUBUNITS AND
FORM AN ACTIVE
ENZYME. SHOWN ON
THE RIGHT IS AN
ACTIVATED SUBUNIT
WITH ITS SUBSTRATE
SHOWN IN RED. SOME OTHER PROTEIN KINASES ARE: PKB (USING A
DERIVATIVE OF INOSITOL) AND PKC (USING CALCIUM)
THE LAST MECHANISM THAT WE WILL LOOK AT INVOLVES
CALCIUM AND CALMODULIN
THIS IS ACTUALLY A DOUBLE MECHANISM THAT REQUIRES TWO
MEMBRANES, TWO ENZYMES AS WELL AS THE USUAL HORMONE,
RECEPTOR PROTEIN AND A G PROTEIN (Gq) TO OPERATE. CALCIUM
AND CALMODULIN PARTICIPATE IN PART OF THE MECHANISM.
HORMONES ASSOCIATED WITH THIS MECHANISM INCLUDE PEPTIDE
HORMONES SUCH AS VASOPRESSIN (POSTERIOR PITUITARY) AND THYROID
RELEASING HORMONE (TRH).
THIS IS A MECHANISM THAT MAKES USE OF PROTEIN KINASE C.
CALCIUM / CALMODULIN MECHANISM:
CASCADE 1
CASCADE 2
SUMMARY
1. PEPTIDE HORMONES VARY FROM A FEW HUNDRED
TO THOUSANDS OF DALTONS IN SIZE.
2. MANY OF THEM ORIGINATE IN THE HYPOTHALMICPITUITARY REGION.
3. EXCEPT FOR THE LARGEST HORMONES (PROTEINS)
THEY DO NOT REQUIRE CARRIERS IN THE BLOOD.
4. PEPTIDE HORMONES BIND TO RECEPTOR PROTEINS
ON THE CELL SURFACE. AFERWARDS, THEY ARE
INTERNALIZED AND DESTROYED.
5. INSULIN IS A PEPTIDE HORMONE THAT IS MADE IN
THE PANCREAS TO TAKE GLUCOSE INTO SPECIFIED
INSULIN DEPENDENT CELLS.
6. IT IS STORED IN INACTIVE FORM. WHEN RELEASED, IT
BINDS TO A RECEPTOR -- AN INACTIVE KINASE.
7. THE KINASE STARTS A CASCADE OF EVENTS AMONG
WHICH IS GLUCOSE UPTAKE.
8. WHEN cAMP (or cGMP) is used as a 2nd messenger, the process
proceeds as follows: hormone > receptor protein > activation of
G protein > activation of adenylyl (guanylyl) cyclase > cAMP (cGMP)
> cascade.
9. CONTROL MECHANISMS ABOUND FOR THIS MECHANISM.
10. WHEN CALCIUM / CALMODULIN ARE USED AS 2ND MESSENGERS,
THE MECHANISM PROCEEDS AS FOLLOWS: HORMONE >
RECEPTOR PROTEIN > ACTIVATION OF G PROTEIN >
ACTIVATION OF PHOSPHOLIPASE C TO RELEASE I tris P
WHILE DAG ACTIVATES PKC ALONG WITH CALCIUM FREED
BY I tris P. CALMODULIN OPERATES THE 2ND CASCADE WHILE
CALCIUM (FREE) OPERATES THE 1ST CASCADE VIA PKC.
WHEW!!