MECHANISM OF HORMONE ACTION€¦ · CLASSIFICATION OF HORMONES 1. ACCORDING TO CHEMICAL NATURE...
Transcript of MECHANISM OF HORMONE ACTION€¦ · CLASSIFICATION OF HORMONES 1. ACCORDING TO CHEMICAL NATURE...
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MECHANISM OF HORMONE ACTION
HORMONE
a chemical messengers
secreted into blood by endocrine cells
transported to distant targets that affect function of other cells. Most hormones circulate in blood, coming into contact with essentially all cells
given hormone usually affects only a limited number of cells, which are called target cells
A target cell responds to a hormone because it bears receptors for the hormone
All hormones act through binding to specific receptors, whether the receptors are located inside the target cell or on the cell surface
The presence of specific receptors on the specific cell types determines how hormones although secreted into the bloodstream affect only certain tissue (receptor specificity)
PREPROHORMONE PROHORMONE PREHORMONE
prohormone derived from larger precursor molecule
not biologically active
cleaved to form prohormone in ER
Inactive until changed into hormone by target cells
Transferred to GA for packaging into secretory vesicles
Molecules secreted by endocrine glands that are inactive until changed into hormone by target cells. Eg : T4 converted to T3.
SIGNAL TRANSDUCTION
process in which cells convert and amplify an extra cellular signal into an intracellular signal.
When a ligand binds to a receptor, it can activate a second protein in the membrane and produce actions.
CELL SIGNALING The mechanism by which cells communicate with one another.
ENDOCRINE ACTION PARACRINE ACTION AUTOCRINE ACTION
hormone is distributed in blood
and binds to distant target
cells.
hormone acts locally by diffusing from its source to target cells in the neighborhood
hormone acts on the same cell
that produced it
SOMATOSTATIN GROWTH FACTORS
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CLASSIFICATION OF HORMONES
1. ACCORDING TO CHEMICAL NATURE STEROID HORMONES NON STEROID HORMONES
AMINO ACID DERIVED PEPTIDE
These hormones are derived from
1. Cholesterol-regulate metabolism
2. Salt/water balance 3. Inflammation 4. Sexual function
Regulate: 1. smooth muscle 2. blood pressure 3. cardiac rate 4. lipolysis 5. glycogenolysis.
1. Regulate many process in all tissues
2. Release of other hormones
Glucorcorticoids
Mineralocorticoids
Sex hormones (adrogens & estrogens)
Cathecholamines
Thyroxin
Melatonin
Large PP
GH
Insulin
glucagon
Small PP
ADH
Glycoproteion (FSH, LH)
2. ACCORDING TO MECHANISM OF ACTION HORMONES THAT BIND TO
INTRACELLULAR RECEPTORS HORMONES THAT BIND TO MEMBRANE RECEPTORS
Lipophylic/ Hydrophobic Hydrophilic
Need transport protein to their target tissue
Don’t need transport protein to reach their target tissues
Plasma half-life : long (hrs-days) Plasma half-life : short (mins)
Onset : slow Onset : fast
Receptors : cytosol or nucleus Receptors : membrane-bound
Form hormone-receptor complex
Affect level of transcription
Binding of hormone to receptor produces 2nd messenger:
(cAMP)
(cGMP)
Protein kinase cascade
Calcium or phosphatidyl inositol or both
Steroid hormones
Thyroid hormones
Calcitriol
Retinoids
FSH
LH
TSH
HCG
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STRUCTURE OF INTRACELLULAR RECEPTORS (STEROID HORMONES) - Lipophilic
STRUCTURE OF CELL SURFACE RECEPTORS (NON STEROID HORMONES) -Hydrophilic
Located in cytoplasm and in the nucleus
Function within the cell to activate
genetic transcription
Messenger RNA directs synthesis of
specific enzyme proteins that change
metabolism
Each nuclear hormone receptor has 2
main regions:
1. A ligand-binding domain
2. DNA- binding domain
Cell surface receptors are integral membrane proteins
with 3 basic domains:
1. Extracellular domains:
Exposed to the outside of the cell interact with
and bind to the hormone
Ligand-binding domain
2. Transmembrane domains:
Serve to anchor the receptor in the membrane
3. Cytoplasmic or intracellular domains:
Tails or loops of the receptor that are within
the cytoplasm react to hormone binding by
interacting in some way with other molecules,
leading to generation of second messengers
Cytoplasmic residues of the receptor are thus
the effector region of the molecule
LOCATION OF HORMONE RESPONSE ELEMETS (HREs)
Located adjacent to gene that will transcibed
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DIMERIZATION process of 2 units coming together at the 2 half sites
stimulates transcription of particular genes.
Mechanism of genomic transcription via nuclear steroid/ thyroid hormone receptors
HORMONES THAT USE SECOND MESSENGERS
Hormones cannot pass through plasma membrane use second messengers
Catecholamine, poplypeptide, and glycoprotein hormones binds to receptor proteins on the
target plasma membrane
Actions are mediated by second messengers (signal-transduction mechanisms)
Extracellular hormones are transduced into intracellular second messengers
SECOND MESSENGER
EXAMPLES OF HORMONES WHICH UTILIZE THIS SYSTEM
CYCLIC AMP PROTEIN KINASE ACTIVITY
CA & PHOSPOHOINOSITIDES
CYCLIC GMP
1. Epinephrine 2.Norepinephrine 3. Glucagon 4. Luteinizing H
5. Follicle SH 6. Thyroid SH 7. Calcitonin 8. PTH 9. Antidiuretic H
1. Insulin 2. Growth Hormone 3. Prolactin 4. Oxytocin 5. Erythropoietin 6. Several GF
1. Epinephrine 2. Norepinephrine 3. Angiotensin II 4. Antidiuretic H 5. Gonadotropin RH 6. Thyroid RH
1. Atrial Natriuretic H 2. Nitric Oxide
1. Lipophilic steroid and thyroid hormones are attached to
plasma carrier proteins
Hormones dissociate from carrier proteins to pass through
lipid component of the target plasma membrane
Receptors for the lipophilic hormones are known as nuclear
hormone receptors
2. Cytoplasmic receptor binds to
steroid hormone
Translocate to nucleus
DNA-binding domain binds to
specific HRE of the DNA
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MECHANISM OF HORMONAL ACTION HORMONES WHICH BIND TO CELL MEMBRANE RECEPTORS
(MOA of Second Messenger System)
These hormones bind to their specific receptors on the cell membrane.
This binding causes the formation of the SECOND MESSENGER.
I. CYCLIC ADENOSINE MONOPHOSPHATE (CAMP) 1. Binding of hormones w receptor allows coupling of receptor to G protein 2. Active G protein stimulates adenylyl cyclase- cAMP system. 3. Stimulated adenylyl cyclase catalyzes the conversion of ATP into cAMP inside cell 4. cAMP then activates cAMP-dependant protein kinase. 5. Active PKa phosphorylates specific proteins in the cell, triggering biochemical reactions that lead to cell’s response to the hormone. Binding Actions of G proteins
G Protein-regulated enzymes and second messenger
Hormone stimulates receptor
→ which activates G Protein (GTP
binding protein)
→ which activates AC
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2. CYCLIC GUANOSINE MONOPHOSPHATE (cGMP)
Guanylyl cyclase maybe in:
3. CALCIUM & PHOSPHOLIPIDS
1. Binding of Epi to a-adrenergic receptor in plasma
membrane activates a G-protein intermediate,
phospholipase C
2. Phospholipase C splits phospholipid into IP3 and DAG
3. Both derivatives serve as second messengers
4. IP3 diffuses through cytoplasm to ER
5. Binding of IP3 to receptor protein in ER causes Ca2+
channels to open
6. Ca2+ diffuses into the cytoplasm & binds to calmodulin
7. Calmodulin activates specific protein kinase enzymes
8. Alters the metabolism of the cell, producing the hormone’s effects
PHOSPHATIDYL INOSITOL
MEMBRANE BOUND FORM
CYTOSOLIC SOLUBLE FORM
Atrial Natriuretic Peptide
NO
Nitroglycerine
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CELL SURFACE RECEPTORS ION CHANNEL LINKED RECEPTORS
The receptor may be part of the ion channel.
1. Changing the electrical properties of a cell through ligand gated channels. 2. Changing cytosolic calcium levels through ligand gated channels
The receptor activation may gate the ion channel
- Action of G protein on a slow ligand gated ion channel
ENZYME LINKED RECEPTORS (protein kinase cascade) ↑
Tyrosine kinases:
Group of enzymes which phosphorylate their substrates on tyrosine residues.
May be:
1. Insulin receptor consists of 2 units that dimerize when they bind
with insulin
2. Insulin binds to ligand-binding site on plasma membrane, activating
enzymatic site in the cytoplasm
3. Autophosphorylation occurs, increasing tyrosine kinase activity
4. Activates signaling molecules
5. Stimulate glycogen, fat and protein
synthesis
6. Stimulate insertion of GLUT-4 carrier
proteins
Intrinsic part of the receptor
Intracellular associated with the receptor
(but not intrinsic part of it)
Insulin receptors Receptors of GH and prolactin