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

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