Mechanisms of hormone actionsMechanisms of hormone actions

Endocrine 412Endocrine 412

ObjectivesObjectives

• Defining hormones hormones and their classifications.classifications.

• Listing the general characteristics of hormones.general characteristics of hormones.

• Identifying factors determining the response of target cells to hormones. factors determining the response of target cells to hormones.

• Describing the different mechanisms of action of hormones.different mechanisms of action of hormones.

• Listing hormones that bind to cell surface receptors. bind to cell surface receptors.

• Listing hormones that bind to intracellular receptors.bind to intracellular receptors.

General characteristics of hormonesGeneral characteristics of hormones

HormonesHormones :• are molecules that are produced by special cells special cells (notnot by all cells of the body)

• are secreted directly to blood directly to blood (with no ducts)

• are available in very low concentrations in bloodin very low concentrations in blood

• are transported in blood to work in distant siteswork in distant sites

• have systemic actionssystemic actions

• have specificspecific receptorsreceptors (either intra- or extra-cellular ) in target tissues

• have different specialspecial mechanisms of actionsmechanisms of actions

Receptors of hormonesReceptors of hormones• Hormones are present in very low concentrations in extracellular fluids (e.g. blood) • In order to initiate their biologic effects, target cells must recognize hormones by

binding to specific receptors • A target cell target cell is defined by its ability to bind selectively a given hormone via a is defined by its ability to bind selectively a given hormone via a

receptorreceptor• Receptors have at least Receptors have at least 2 DOMAINS2 DOMAINS:

1- RecognitionRecognition domaindomain: binds to the hormone

2- CouplingCoupling domaindomain: couples hormone recognition to some intracellular function by

generating a signal

Generally, COUPLING occurs by two ways:Generally, COUPLING occurs by two ways:1- Polypeptide hormones, protein hormones & catecholamines binding of hormones to

plasma membrane receptors (extracellular receptorsextracellular receptors).

2- Steroid & thyroid hormones interact with intracellularintracellular receptorsreceptors, form complexes that

generates a signal.

1-Rate of production:1-Rate of production:

Synthesis and secretion of hormones are the most highly regulated aspect of

endocrine control. Such control is mediated by positive and negative feedback circuits

The concentration of hormone as seen by target cells is The concentration of hormone as seen by target cells is determined by three factorsdetermined by three factors::

2-Rate of delivery2-Rate of delivery: : An example of this effect is blood flow to a target organ or group of target cells – high blood flow delivers more hormone than low blood flow.

3-Rate of degradation and elimination:3-Rate of degradation and elimination: Hormones, like all biomolecules, have characteristic rates of decay, and are metabolized and excreted from the body through several routes.

Hormones are cleared byHormones are cleared by:

1- Metabolic destruction by tissues2- Binding with tissues3- Excretion by the liver into bile4- Excretion by the kidney into urine5- Clearance of protein bound hormones is slower than clearance of peptide hormones

The concentration of hormone as seen by target cells is The concentration of hormone as seen by target cells is determined by three factors: determined by three factors: (cont.)

Classifications of hormonesClassifications of hormonesHormones are classified accordingaccording to:

1- 1- ChemicalChemical composition composition (protein or others)(protein or others)

2- 2- SolubilitySolubility (hydrophilic or lipophilic) (hydrophilic or lipophilic)

3- 3- LocationLocation of receptors (intra- or extra-cellular) of receptors (intra- or extra-cellular)

4- Nature of 4- Nature of signalsignal used to mediate hormone action within cells used to mediate hormone action within cellsAccording to their classifications, hormones are classified into

Group IGroup I & Group II Group II (according to mechanism of actionaccording to mechanism of action)

Classification of hormones according to mechanism of action:Classification of hormones according to mechanism of action:

Group IGroup IHormones that bind to intracellular receptors (cytosolic or nucleus)intracellular receptors (cytosolic or nucleus):1- SolubilitySolubility: lipophilic (to pass cell membrane which is mainly lipid)

2- Chemical compositionChemical composition:

Derived from cholesterol (except: thyroid hormones & retinoic acid)

3- Transport in bloodTransport in blood:

Associate with transport proteins (to tackle solubility problem)

Long plasma half-life

4-Mechanism of action4-Mechanism of action:

1- Free hormone traversestraverses plasma membrane of cells & binds to receptorreceptor in cytosol or nucleus of target cells.

2- Hormone-receptor complex binds to specific region in DNA of gene (hormone-response element, HREHRE)

3- Binding causes activation or inactivation of specific gene(s) transcriptiontranscription (production of mRNA)

4- Accordingly, amount of protein synthesisprotein synthesis (production) is changed (protein may be enzymes of metabolic react.)

5- Accordingly, certain metabolic processes are affected.

Example of Example of Group IGroup I hormones: hormones: Steroid hormones via cytoplasmic receptorsSteroid hormones via cytoplasmic receptors

Example of Example of Group IGroup I hormones hormones: : Retinoic acid Retinoic acid (active product of vitamin A)(active product of vitamin A) via nuclear receptors via nuclear receptors

List of List of Group I Group I hormoneshormones

• Thyroid hormonesThyroid hormones

• Steroid hormones:Steroid hormones: Glucocorticoids Glucocorticoids (e.g. cortisol hormone)(e.g. cortisol hormone) Mineralocorticoids Mineralocorticoids (e.g. aldesterone)(e.g. aldesterone) Androgens Androgens (e.g. testosterone hormone)(e.g. testosterone hormone) EstrogensEstrogens Progestins Progestins (e.g. progesterone hormone)(e.g. progesterone hormone)

• Retinoic acid Retinoic acid (active metabolite of vitamin A)(active metabolite of vitamin A)

• CalcitriolCalcitriol (1, 25 DHCC, active metabolite of vitamin D)(1, 25 DHCC, active metabolite of vitamin D)

Hormones that bind to plasma membrane (extra-cellular) receptorsplasma membrane (extra-cellular) receptors:1- SolubilitySolubility: hydrophilic2- Chemical compositionChemical composition: Polypeptides, proteins, glycoproteins & catecholamines3- Transport in bloodTransport in blood: No transport protein- short plasma half-life4-MechanismMechanism of actionof action: Hormone binds to plasma membrane receptor Hormone -receptor interaction leads to generation of secondsecond messengermessenger

intracellularly that communicates (couples) hormones binding with intracellular metabolic processes

Second messengersSecond messengers::1- cyclic AMP (cAMP)2- cyclic GMP (cGMP)3- Calcium or phosphaitdyl inosiltol (or both)4- Kinase cascade

Classification of hormones according to mechanism of action:Classification of hormones according to mechanism of action:

Group IIGroup II

Second Messenger: cAMPSecond Messenger: cAMP

1- Second messenger is 1- Second messenger is cAMPcAMP::

2adrenergicCatecholaminesAdrenocorticotropic Hormone (ACTH)Angiotensin IIAntidiuretic Hormone (ADH)CalcitoninHuman Chorionic Gonadotropins (hCG)Corticotropin-releasing hormone (CRH)Follicle Stimulating Hormone (FSH)Leutinizing Hormone (LH)GlucagonIpotropin (LPH)MSH (Melanocyte Stimulating Hormone)Parathyroid Hormone (PTH)SomatostatinThyroid Stimulating Hormone (TSH)

List of List of Group II Group II hormoneshormones

1- 1- Second messenger is Second messenger is cGMPcGMP

Atrial natriuretic peptide (ANP)Nitric Oxide (NO)

There are two isoforms of guanylate cyclase involved in production of cGMP:• A membrane-bound membrane-bound guanylate cyclase ( for ANP & bacterial endotoxin)• A cytosolic cytosolic guanylate cyclase (for NO)

List of List of Group II Group II hormoneshormones

Second messenger cGMP:Second messenger cGMP:Atrial Natriuretic PeptideAtrial Natriuretic Peptide

Nitric Oxide Synthase

NO•

Binds to heme moiety of guanylate cyclase

Conformational change of the enzyme

Increased activity (production of cGMP)

Modulation of activity of other proteins (protein

kinases, phospho-diesterases, ion

channels)

Physiological response (relaxation of smooth muscles, inhibition of platelet aggregation,

etc.)

NO• signaling in physiology

O2-• ONOO-

Second Messenger: Phosphatidyl inositol & Second Messenger: Phosphatidyl inositol & calciumcalcium

Second messenger is Second messenger is phosphatidyl inositol or calcium phosphatidyl inositol or calcium (or (or both together)both together)

Acetylcholine 1 adrenergic catecholaminesAngiotensin IIAntideuretic Hormone (ADH)CholecystokininGastrinGonadotropin –Releasing Hormone (GnRH)OxytocinPlatelet Derived Growth Factor (PDGF)Substance PThyrotropin Releasing Hormone (TRH)

List of List of Group II Group II hormoneshormones

Binding of insulin on -subunits

Of insulin receptors

Phosphorylationof -subunits

Of insulin receptors

Phosphorylationof insulin response substrates (IRS)

CHANGEIN

Gene Metabolism GrowthExpression

Second Messenger: Kinase cascadeSecond Messenger: Kinase cascade (for insulin hormone) (for insulin hormone)

Second messenger is Second messenger is kinase cascadekinase cascade::

Chorionic somatomammotropin (CS)Epidermal Growth factor (EGF)Erythropoeitin (EPO)Antideuretic Hormone (ADH)Fibroblast Growth Factors (FGF)Growth Hormone (GH)InsulinInsulin-like Growth factors (IGF-I & IGF-II)Nerve Growth Factor (NGF)Platelet Derived Growth Factor (PDGF)Prolactin (PRL)

List of List of Group II Group II hormoneshormones