BASIC PRINCIPLE OF ENDOCRINE SYSTEM
INTRODUCTION
• Endocrine(Gk- I separate within)• Chemical messenger system-i. Neurotransmittersii. Endocrine hormonesiii. Neuroendocrine hormonesiv. Paracrinesv. Autocrinesvi. Cytokines
HISTORY• Arnold A Berthold (1849)- effect of testosterone on rooster.
• Claude Bernard (1854)- internal mileu
• Ernest Henry Starling (1902)- with Bayliss demonstrated that secretin stimulates pancreatic secretion.
He was the first to use the term hormone (to excite)
• SIR THOMAS BEATSON- progress of BREAST cancer can be delayed by removing ovaries (estrogen)
• EARL WILBUR SUTHERLAND Jr.(1971)- discovery of second messenger
• BERSON AND YALOW(1960s)- radioimmunoassay
• DALY et al.(1974)- Cytochemical assays
LOCATION OF ENDOCRINE GLANDS
ORGAN HORMONES
HEART ANP
GIT CCK-PZ, SECRETIN, VIP
KIDNEY ERYTHROPOIETIN, 1,25-DHCC
PINEAL GLAND MELATONIN
SKIN CALCIFEROL(Vit-D3)
LIVER IGF-I, II
PLATELET PDGF
LYMPHOCYTES IL
HORMONES• Gk :Horman= to set in motion
• DEFINITION
• CHARECTERESTIC-i. Distant target cellii. Receptoriii. Regulates existing fundamental bodily process but do not initiate
cellular reaction.iv. Secreted in extremely low concentrationv. Long latent period than neurons.vi. Metabolized rapidly in kidney and liver
• CHEMISTRY-1) Peptide Hormone
Figure 7-3
4 5
To target
Active hormone
Golgi complex
Secretoryvesicle
ECFCytoplasm Plasma
Peptidefragment
Releasesignal
Capillaryendothelium
Messenger RNA on the ribosome binds amino acids into a peptide chain called a preprohormone.The chain is directed into the ER lumen by a signal sequence of amino acids.
The secretory vesicle releases its contents by exocytosis into the extracellular space.
The hormone moves into the circulation for transport to its target.
Enzymes in the ER chop off the signal sequence, creating an inactiveprohormone.
The prohormone passes from theER through the Golgi complex.
Secretory vesicles containing enzymes and prohormone bud off the Golgi. The enzymes chop the prohormone into one or more active peptides plus additional peptide fragments.
mRNA
Ribosome
Prohormone
Signalsequence
Transportvesicle
Endoplasmic reticulum (ER)
Preprohormone
1 2 3 6
1
2
3
4
5
6
2) Steroid Hormones
Steroid hormones are derived from cholesterol
Figure 7-6
3)Amine Hormones: Structure
Tyrosine-derived amine hormones
Figure 7-8
Hormone Transport
Unbound to plasma protein Water soluble hormones Catecholamines,peptides &protein hormones.
Bound to plasma protein Lipid soluble hormones Steroid –SBP Testosterone and estrogen- SHBG Progesterone, cortisol and other corticosteroid-
TRANSCORTIN
Free hormone is the active hormone.
Plasma ConcentrationHormones are secreted in very low concentration in
pulsatile manner.
RYTHMS:-1. CIRCADIAN(Diurnal)2. ULTRADIAN
Half- Life of some Hormones
Class of Hormone Hormone Half- Life
Protein & Peptide Hormones
•ADH•Oxytocin•Insulin•Prolactin•Growth Hormone
<1 min<1 Min5 min12 sec<30 min
Amines •Epinephrine•Thyroxin
10 sec5-7 days
Steroid Hormones •Aldosterone•Cortisol
30 Min90-100 Min
Hormone Disposal1. Target cell uptake & Intracellular degradation.2. Metabolic degradation by Liver & Kidney3. Urinary & Biliary Disposal
Metabolic clearance rate (MCR) • Defines the quantitative removal of hormone from plasma • The bulk of hormone is cleared by liver and kidneys • Only a small fraction is removed by target tissue
– protein and amine hormones bind to receptors and are internalized and degraded
– Steroid and thyroid hormones are degraded after hormone-receptor complex binds to nuclear chromatin
MCR = Rate of disappearance of hormone from plasma / ( ml cleared/ minute ) Concentration of
hormone
Receptors
Characteristic Of Hormone ReceptorsSpecificityLocation 1. Internal 2. ExternalAffinityDensityRegulation 1.Up 2. DownSpare Receptor
Spare receptors
• In most systems the maximum biological response is achieved at concentrations of hormone lower than required to occupy all of the receptors on the cell.
• Examples: – insulin stimulates maximum glucose oxidation in
adipocytes with only 2-3% of receptors bound– LH stimulates maximum testosterone production in Leydig
cells when only 1% of receptors are bound• Maximum response with 2-3% receptor occupancy.
97% of receptors are “spare
Classification of Membrane Receptor
Protein tyrosine kinase receptors
Second messengers for cell-surface receptors
Second messenger systems include: Adenylate cyclase which catalyzes the conversion of ATP to
cyclic AMP,
Guanylate cyclase which catalyzes the conversion of GMP to cyclic GMP (cyclic AMP and cyclic GMP are known collectively as cyclic nucleotides)
Calcium and calmodulin; phospholipase C which catalyzes
phosphoinositide turnover producing inositol phosphates and diacyl glycerol.
Functions of Hormones
1. Help regulate: Chemical composition & volume of
internal environment. Metabolism & Energy balance. Contraction of smooth muscle & cardiac
muscle fiber. Glandular secretion. Immune system activities.
2. Control Growth & Development
3.Regulate operation of reproductive system.
4.Help establish circadian rhythms.
REGULATION OF HORMONES
• Direct control (substances)• Nervous control (neurosecretion)• Feedback control (Hormone concentration)• Chronotropic control
Neural Control
• Release of Oxytocin, which fills the milk ducts in response to the stimulus of suckling.
• Release of Aldosterone, which augments the circulatory volume in response to upright posture.
• Release of Melatonin in response to darkness.
Feedback Loops
Figure 6-26: Negative and positive feedback
Negative Feedback Controls
Figure 7-14
Ultra short loop fb
Chronotropic Control
• Pulsatile release of hormone.• Diurnal variation.• Sleep Wake Cycle variation.• Menstrual Rhythm.• Seasonal Rhythm• Developmental Rhythm.
MECHANISMHormone+ Receptor
Conformational change in the receptor(SIGNAL)
TransducedActivation of one or more intracellular messenger
(TRANSDUCTION)
Messenger molecule bind to effector proteins
Regulate/ modify specific cellular function(CELLULAR RESPONSE)
SIGNAL TRANSDUCTION PATHWAY/ SIGNALLING PATHWAY
VARIOUS MODES OF INFORMATIONAL CONDUCTION AND TRANSFER BY SIGNALLING PATHWAY –
1. Covalent phosphorylation of proteins and lipids2. Non-covalent GTP binding to G-proteins3. Non-covalent binding of cyclic nucleotide monophosphate4. Non-covalent Ca++ binding and activation of proteins5. Generation of lipid information molecules
1.
2- GPCR+ GDP- INACTIVE, GPCR+ ATP- ACTIVEGEFs G-protein
Inactivation of G-protein by- i) Intrinsic GTPase activity ii) Regulator of G protein signalling (RGS)
3- 4-
GTP GDP
GTP NO GUANYLYL CYCLASE
cGMP
PKG [Ca++]ICF
cGMP GMP
SILDENAFIL (VIAGRA)
PHOPHODIESTERASE
4-GENERATION OF LIPID INFORMATION MOLECULE-
IP3, DAG
PIP3
DAG
IP3
(PHOSPHATIDYL INOSITOL 3 KINASE)
1-RECEPTORS USING G PROTEIN• Signaling from membrane receptors
Modulation of levels of intracellular messenger-cAMP-DAG-IP3
Cellular response
2-RECEPTOR TYROSINE KINASE
• Gp 1-Growth factors (PDGF, EGF)
• Gp 2-Insulin & IGF
(ERKs)
GF
3-ENZYME LINKED RECEPTORS ASSOCIATED WITH CYTOPLASMIC TYROSINE KINASE
EXAMPLE-• Growth hormone• Prolactin• Erythropoietinleptin • Leptin JAK-Janus Kinase 2
STAT-Signal Transducer and Activator of Transcription
SOCS-Suppressors Of Cytokine Signaling
4-RECEPTOR SERINE/THREONINE KINASE
TGF β related hormones
• Anti-mullerian hormone
• Inhibin
5-Receptors regulating ion channel
• Calcium channel
Signaling from intracellular receptor-
• Steroid hormone• Thyroid hormone• 1,25-DHCC• Vit-A,D,E,K, Retinoic acid
Nuclear receptor superfamily- 3 domains-i) Aminoterminus domain- hormone independent transcriptionii) DNA binding domain- 2 Zn finger motif Zn finger motif+ Neighboring A.A.= HRE (recognize and bind specific DNA
sequence)iii) Carboxyl termina domain-subdomains-
a)a site of hormone recognition & bindingb)a hormone dependent transcriptional activation domainc)a nuclear translocation signald)a binding domain for HSP (Chaperone)e)a dimerization subdomain.
Pathway-1Cytoplasmic/nuclear receptor
Pathway 2- • Only nuclear receptor• TR, RXR, Vit-D
HDAC
Hormone assay
• Radioimmunoassay • ELISA
APPLIED
Hormone deficiency •Congenital- CAH•Autoimmune- Type l DM•Iatrogenic
Hormone excess •Tumor - Gigantism•Autoimmune- Grave’s Ds
Hormone resistance •Receptor defect- Type ll DM
Second messenger defect
• Atopic dermatitis
THANK YOU
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