hormone action (other than insulin & steroids) endocrinology rounds july 29, 2009 selina liu...

Hormone Action(Other than Insulin & Steroids)

Endocrinology RoundsJuly 29, 2009

Selina LiuPGY4 Endocrinology

Outline

Definitions

Hormone Classification & Structure

Hormone Synthesis & Release

Mechanisms of Action

Site of Action & Receptors

Endocrine Disorders & Pathophysiology

Definitions

endocrine – derived from Greek

endo “within” krinein “to separate”

internal secretion of biologically active substances

act on target cells to cause effect

Greenspan FS & Gardner DG (eds) Basic & Clinical Endocrinology 7th Edition 2004

Definitions

hormone – derived from:

hormao - “I excite or arouse”

Ernest Starling – 1905Croonian Lectures of the Royal College of

Physicians

Henderson, J. J Endocrinol 2005;184: 5-10

Ernest StarlingApril 17, 1866-May 2, 1927

Professor of PhysiologyUniversity College London

Also known for:

Starling’s Law discovery of peristalsis discovery of secretin (with William Bayliss)

Henderson, J. J

Endocrinol 2005;184: 5-10

Outline

Definitions






Classification

classified by structure

protein/peptide hormones amino acid derivatives

tyrosine derivatives tryptophan derivatives

lipid-derived hormones cholesterol derivatives - steroid hormones phospholipid derivatives - eicosanoids

Protein & Peptide Hormones

can be: direct translation products of specific mRNAs cleavage products of larger precursor proteins modified peptides

variable sizee.g. TRH – 3 amino acids hCG – 237 amino acids


TRH3 amino acids

hCG237 amino acids


often produced as large inactive precursors (“prohormone”)

require cleavage by proteases for activation

i.e. endothelin-1

www.bioscience.org/2003/v8/e/1103/fig4.jpg


other examples:

hypothalamic hormones GHRH, GnRH, TRH, CRH, AVP, PRF, DA, somatostatin

pituitary hormones GH, LH, FSH, TSH, ACTH, PRL, oxytocin

pancreatic hormones insulin, glucagon, somatostatin, pancreatic polypeptide

calcium-regulating hormones PTH, calcitonin


other examples:

reproductive hormones inhibin, oxytocin, hCG

plasma volume/sodium-regulating hormones

ANP, AVP, renin, angiotensin

CV hormones endothelins, EPO, bradykinin

growth factors/cytokines IGF, EGF, interleukins, TNF-

Amino Acid Derivatives

Tyrosine Derivatives

i.e. catecholamines dopamine thyroid hormones

http://www.colorado.edu/intphys/Class/IPHY3430-200/image/23-8.jpghttp://www.rpi.edu/dept/bcbp/molbiochem/BiochSci/sbello/tyr_norep.gif

Amino Acid Derivatives

Tryptophan Derivatives

i.e. melatonin

seratonin

Lipid-Derived Hormones

Steroid Hormones

derived from cholesterol (C27)

major groups: progestins glucocorticoids mineralocorticoids androgens estrogens

http://www.gfmer.ch/Books/Reproductive_health/Steroid_hormone_metabolism_Fig2.html

Lipid-Derived Hormones

Eicosanoids

derived from phospholipids

i.e. arachidonic acid (C20 “eikos”)

major groups: prostaglandins thromboxanes leukotrienes

http://www.ufrgs.br/laprotox/eicosanoids-eng.htm

Outline

Definitions






Hormone Synthesis

Peptide Hormones(see next slides)

Amino Acid Derivatives synthesized via side-chain modifications of tyrosine or tryptophan

Lipid Derivatives steroids – (as per Rola’s talk last week) eicosanoids – derived from arachidonic acid

Hormone Release

Vesicle-Mediated peptide hormones some nonpeptide hormones/neurotransmitters

i.e. catecholamines, ACh, GABA

Non-Vesicle Mediated steroids eicosanoids

Peptide Hormone Synthesis & Release

Nussey SS & Whitehead SA. Endocrinology An Integrated Approach 2001

occurs in cytoplasm

vesicle-mediated

via classical “secretory pathway”

Peptide Hormone Synthesis


Targeted to ER lumen via signal recognition particle

in Golgi apparatus,prohormone is cleaved into smaller peptides, stored in secretory granules

Peptide Hormone Release

stimulus for secretion may or may not be coupled with stimulus for synthesis

often synthesized and stored for later release

stimulus for secretion triggers fusion of secretory vesicle membrane with plasma membrane

release of vesicle contents by exocystosis


Non-Vesicle Mediated Release

steroids – derived from cholesterol synthesized in adrenals, gonads, placenta

also in nervous system, other tissues

eicosanoids – derived from arachidonic acid not stored by cells arachidonic acid precursor stores in membrane lipids

formation catalyzed by PLA2 or PLC cleave esterified arachidonic acid from the 2 position of glycerophopholipids in the lipid bilayer of cell


Steroid Hormone Synthesis


Eicosanoid Synthesis


Outline

Definitions






Hormone Actions

fetal development cell growth & cancer intermediary metabolism

CHO, fat, protein, amino acid, nucleic acid mineral & water metabolism cardiovascular/renal function skeletal function reproductive function immune system CNS regulation of hormone production/release

Site of Actions

Endocrine effect – classical definition:

chemicals released by ductless gland into circulation* act on specific receptor on distant* target cell

*ALSO : paracrine/juxtacrine effects – on adjacent cells autocrine effects – act on same cell intracrine effects – within same cell neuroendocrine effects

Mechanism of Action

At Organ-System Level:

Free-standing endocrine glands i.e. parathyroid gland

Hypothalamic-Pituitary-Target Gland systems

i.e. Hypothalamic-Pituitary-Thyroid axis

Free-Standing Gland

Gland

Target Cell

Hormone

EFFECT

i.e. Parathyroid Gland

Parathyroid Gland

Target Cells

PTH

Increase in serum calcium

i.e. bone, intestine, kidney

Hypothalamic-Pituitary-Target Axis

Hypothalamus

Pituitary

Releasing Hormone

Trophic Hormone

Gland

Hormone

Target Cell

EFFECT

-

-

Hypothalamic-Pituitary-Thyroid Axis

Hypothalamus

Pituitary

TRH

TSH

Thyroid

T4/T3

Target Cells

EFFECT

-

-

Mechanism of Action

At Molecular Level:

classified by receptor type at which they act

cell-surface receptors

intracellular receptors cytoplasmic or nuclear

Cell-Surface Receptors

bind hydrophilic hormones

activate signal transduction cascade involves generation of 2nd messengers or protein phosphorylation cascades

Mayo KE in Melmed S & Conn PM (eds) Endocrinology: Basic & Clinical Principles 2nd Edition 2005


very diverse group of receptors

common feature: presence of > 1 hydrophobic membrane-spanning domains which anchor receptor at cell surface

extracellular regions – hormone binding intracellular regions – direct enzymatic action or associate with intermediary proteins


1)G-Protein Coupled Receptors2)Receptors with Protein Kinase Activity either intrinsic activity or recruit and activate

protein kinases

3) Receptors with Guanylyl Cyclase Activity (intrinsic)

4) TNF Receptors 5) Transport Receptors


G-Protein Coupled Receptors

GPCRs – largest family of cell surface receptors

7 transmembrane spanning domains heptahelical or serpentine

coupled to G-protein comprised of G subunit and subunit

on ligand-binding, exchange bound GDP for GTP on associated G subunits

i.e. -adrenergic receptor

G-Protein Coupled Receptors

http://www.sigmaaldrich.com/life-science/cell-biology/learning-center/pathway-slides-and.html

Receptors with Protein Kinase Activity

Receptor Tyrosine Kinases cytoplasmic domains have intrinsic

tyrosine kinase activity i.e. insulin receptor, EGF-R, PDGF-R

TGF Superfamily Receptors cytoplasmic domains have intrinsic

serine or threonine kinase activity

Cytokine Receptor Superfamily recruit soluble protein tyrosine kinases of

Janus kinase family (JAKs) i.e. receptors for GH, PRL, interleukins

http://kph12.myweb.uga.edu/11_8tyrosinekinase.jpg

Receptor Tyrosine Kinases

Receptors with Guanylyl Cyclase Activity

single chain transmembrane proteins cytoplasmic domains with intrinsic

guanylyl cyclase (GC) activity promote production of cyclic GMP

related to, but distinct from, soluble GCs

7 receptors: GC-A to GC-G GC-A binds ANP, BNP

TNF Receptors

large and diverse family of receptors (~30)

mediate action of TNF

homologous extracellular domains classified into 2 groups based on

intracellular domain those containing death domain those lacking death domain

both groups mediate signalling leading to apoptosis

Transport Receptors

serve to transport substances from plasma to cell as opposed to activating classic

signalling pathways

bind ligand, cluster into coated pits and are endocytosed into vesicles ligand dissociated & utilized, receptor

either degraded or recycled

i.e. LDL receptor, transferrin receptor

Intracellular Receptors

bind hydrophobic hormones that enter cell directly by diffusion across lipid bilayer

cytoplasmic or nuclear receptors are ligand-activated transcription

factors directly mediate gene transcription

Intracellular Receptors

main group - nuclear receptor superfamily

receptors for: steroids, thyroid hormone, vitamin

D, PPAR large number of orphan receptors

mediate genomic and nongenomic effects

Outline

Definitions






Endocrine Disorders

wide spectrum

from incidental finding to life-threatening metabolic derangements

variety of pathophysiologial mechanisms

many disorders have multiple mechanisms

large phenotypic variation in clinical manifestations

Heaney AP & Braunstein GD in Melmed S & Conn PM (eds) Endocrinology: Basic & Clinical Principles 2nd Edition 2005

Pathophysiology of Endocrine Disorders

congenital vs. acquired

asymptomatic vs. hypofunction vs. hyperfunction

can occur at multiple levels i.e. gene, hormone, receptor, tissue…..

Heaney AP & Braunstein GD in Melmed S & Conn PM (eds) Endocrinology: Basic & Clinical Principles 2nd Edition 2005

Hyperfunction

Hypofunction

Outline

Definitions






References Greenspan FS & Gardner DG (eds) Basic & Clinical Endocrinology 7th Edition 2004

Henderson, J. J Endocrinol 2005;184: 5-10


Melmed S & Conn PM (eds) Endocrinology: Basic & Clinical Principles 2nd Edition 2005

http://www.bioscience.org/2003/v8/e/1103/fig4.jpg

http://www.rpi.edu/dept/bcbp/molbiochem/BiochSci/sbello/tyr_norep.gif

http://www.colorado.edu/intphys/Class/IPHY3430-200/image/23-8.jpg



http://www.sigmaaldrich.com/life-science/cell-biology/learning-center/pathway-slides-and.html

http://kph12.myweb.uga.edu/11_8tyrosinekinase.jpg

hormone action (other than insulin & steroids) endocrinology rounds july 29, 2009 selina liu...

Documents

hormones pth

hormones anp

reproductive hormones

hypothalamic hormones

slides amino acid derivatives

hormone actionother

amino acids hcg

j endocrinol