Download ppt - Hormone Metabolism

BELLA MARILOU BAXA-DAGUPLO, MDBELLA MARILOU BAXA-DAGUPLO, MD

Department of Biochemistry & NutritionDepartment of Biochemistry & NutritionFatima College of MedicineFatima College of Medicine

Our Lady of Fatima UniversityOur Lady of Fatima University

(Review ’09)

HormonesHormones from the Greek termfrom the Greek term ((ὁρμήὁρμή ) "impetus“ ) "impetus“

- “to arouse to activity”- “to arouse to activity”

substance synthesized in one tissue & transported substance synthesized in one tissue & transported by circulatory system to act on another organby circulatory system to act on another organ

“ON”

“OFF”

Targetcell

Cellorigin

(Effects)

Hormone Metabolism

Hormone Metabolism

EndocrineEndocrine ParacrineParacrine AutocrineAutocrine

Functions of HormonesFunctions of Hormones

Hormone and Neurotransmitters… Hormone and Neurotransmitters…

Hormone Metabolism

Norepinephrine/Serotonin → depression

oversensitivity to serotonin → OCD behaviors

Dopamine → Parkinson’s disease

Too much dopamine in the limbic system and not enough in the cortex → personality given to bouts of paranoia or (-) social interaction

norepinephrine (NE)→ aggression

Hormone and Neurotransmitters… Hormone and Neurotransmitters…

Hormone Metabolism

Phenylethylamine + dopamine → mild anti-depressant effect

Phenylethylamine in the limbic system → “feelings of bliss”

oxytoxin → impulse to “cuddle”; multiple orgasm

norepinephrine w/ dopamine & phenylethylamine → give us the feeling of infatuation

too much stress in children can create permanently levels of serotonin and levels of NE → creating a potential of violent behavior

Hormone Metabolism

General General Characteristics Characteristics

of Hormonesof Hormones Not secreted at a uniform rateNot secreted at a uniform rate Exert their effects in biocatalytic amountsExert their effects in biocatalytic amounts Turnover is varied and usually rapidTurnover is varied and usually rapid Exert multiple actionsExert multiple actions Exhibit high degree of specificityExhibit high degree of specificity Different tissues may respondDifferent tissues may respond

differently to a given hormonedifferently to a given hormone

Regulation of Hormone SecretionRegulation of Hormone Secretion

A. Feedback ControlA. Feedback Control1) Negative Feedback2) Positive Feedback

Hormone Metabolism

B. Neural ControlB. Neural Control- visual/ olfactory/ gustatory

C. Chronotropic ControlC. Chronotropic Control- sleep-wake cycle/ physiologic cycle

Regulation of Hormone SecretionRegulation of Hormone Secretion……

Hormone Metabolism

Feedback ControlFeedback Control

Negative Feedback

T3 and T4 inhibits secretion of TRH and TSH

HPT AxisHPT Axis

Hypothalamus

TRH

TSH

T3 , T4

+-

+

+

-

AnteriorPituitary

Thyroid

Increasedmetabolism

Regulation of Hormone SecretionRegulation of Hormone Secretion……

Hormone Metabolism

Feedback ControlFeedback Control

Positive Feedback

Female HPG AxisFemale HPG Axis

+

+

Hypothalamus+

AnteriorPituitary

Ovaries

Estrogen Progesterone

+

+

+

-

- FSHLH

GnRH

estrogen level results to LH surge during ovulation

Forms of Hormone in theForms of Hormone in theCirculationCirculation

Hormone Metabolism

A. Free Molecules (unbound)A. Free Molecules (unbound)- water-soluble hormones

B. Bound MoleculesB. Bound Molecules- water insoluble hormones- bound with specific globulins or transport proteins such as albumin, “cortisol-binding globulin”, and “thyroid-binding globulin”

Fates of HormoneFates of Hormone

Hormone Metabolism

A. Target cell uptakeA. Target cell uptake

B. Metabolic degradationB. Metabolic degradation

C.C. Urinary or biliary excretionUrinary or biliary excretion

kidney and liver are the major sites of hormone metabolism and degradation

Classification of HormonesClassification of Hormones

I. According to StructureI. According to StructureA. Protein hormones

1) Simple or polypeptide [insulin, glucagon, somatostatin, growth h., ACTH, MSH, PRL, CS …]

2) Complex or glycoprotein [TSH, FSH, LH, hCG…]

B. Steroid hormones [glucocorticoids, mineralocorticoids, sex androgens, retinoic a., calcitriol…]

C. Biogenic amine hormones [thyroxine,catecholamines]

II. According to Mechanism of ActionII. According to Mechanism of ActionA. Group 1B. Group 2

Hormone Metabolism

Hormone Metabolism

Classification of HormonesClassification of Hormones…… [Protein]

Insulin and C-peptide Formation

Ribosome ER Golgi A. Vesicles

A-Chain

B-Chain

Hormone Metabolism

Pro-opiomelanocortin Peptide Family

Classification of HormonesClassification of Hormones…… [Protein]

Hormone Metabolism

Classification of HormonesClassification of Hormones…… [Steroids]

Classification of HormonesClassification of Hormones…… [Amines]

Hormone Metabolism

Some Biogenic Amines

Dopamine

CH2 - CH2 – NH2 HO

HO

CH - CH2 – NHCH3

OH

HO

HO

Epinephrine Tetraiodothyronine

Norepinephrine

CH - CH2 – NH2

OH

HO

HO

Classification of HormonesClassification of Hormones

Hormone Metabolism

Group 1 Group 2

Type Steroids, thyroid h., Polypeptides and retinoic acid …. catecholamines…

Solubility Lipophilic Hydrophilic

Transport Protein Yes No

Plasma T1/2 Longer Shorter

Receptor Intracellular Plasma membrane

Mediator HRC/HRE 2nd messengers

According to Mechanism of ActionAccording to Mechanism of Action

Hormone Metabolism

Steps Involved in ElicitingSteps Involved in ElicitingResponse of Target CellResponse of Target Cell

1)1) Recognition and binding of the hormoneRecognition and binding of the hormoneto specific receptorto specific receptor

2) Coupling to generate signal2) Coupling to generate signal

3)3) Changes in intracellular processesChanges in intracellular processesbrought about by the generated signalbrought about by the generated signal

Hormone Metabolism

ReceptorsReceptors

specific proteins that must first bind aspecific proteins that must first bind a hormone before cellular response canhormone before cellular response can be elicitedbe elicited

have at least 2 Functional domains:have at least 2 Functional domains:

1) Recognition domain - binding domain 2) Coupling domain - generates signal that

couples hormone recognition to someintracellular function

Hormone Metabolism

Classes:Classes:

A. Cell surface receptors

B. Intracellular receptors

1) Nuclear receptors2) Cytoplasmic receptors

ReceptorsReceptors

Cell Membrane ReceptorsCell Membrane Receptors

Functional Domains:Functional Domains:

1) Ligand-binding domain 2) Transmembrane domain 3) Cytoplasmic domain

Hormone Metabolism

ReceptorsReceptors

N

C

Typical cell membrane receptor(seven membrane-spanning domain)

Extracellular

Intracellular

Intracellular ReceptorsIntracellular Receptors

Functional Domains:Functional Domains:

1) A hormone bindinghormone binding region in the C-terminal 2) An adjacent DNA bindingDNA binding region 3) A specifier regionspecifier region (N-terminal) necessary for

high-affinity binding to the proper region ofDNA

4) One or more regions that activate or repressactivate or repressgene transcriptiongene transcription

Hormone Metabolism

ReceptorsReceptors

(1)(2)(3)

N C

Hormone Metabolism

Signal TransductionSignal Transduction

process which occurs after a hormoneprocess which occurs after a hormone binds to a receptorbinds to a receptor

an intracellular signal is generatedan intracellular signal is generated [second messenger][second messenger] which delivers which delivers the hormonal messagethe hormonal message

amplifies the original signal convertingamplifies the original signal converting substrate molecules to productssubstrate molecules to products

Hormone Metabolism

Signal TransductionSignal Transduction

PeptidesCatecholamines

Neurotransmitters…Steroids

Thyroid hormonesEstrogen, RA…

Insulin, EGF, IGF-1

Growth hormoneProlactin…

Signal Transduction PathwaysSignal Transduction Pathways

Enzyme Activation Nucleus

Hormone Metabolism

Mechanism of Action… Mechanism of Action… [Group 1][Group 1]

CytoplasmNucleus

Hormone Action with intracellular receptorsHormone Action with intracellular receptors

+

“Activation”

+

Specific Protein

TranscriptionmRNA

TranslationmRNA

Metabolic response

Hormone response element (HRE)

Hormone receptor complex (HRC)

ReceptorSteroid/Thyroid h.

Thyroid h.

Hormone Metabolism


Structural requirements for hormonal regulation of gene transcription

5’ 3’

Hormone responseelements (HRE)

Promoterelement (PE) Gene

TranscriptionInitiation site

TerminationSite

1+

Regulatory DNA region Structural DNA region

Hormone Metabolism


Hormones that bind to Intracellular receptorsHormones that bind to Intracellular receptors(Group 1)(Group 1)

Mineralocorticoids Glucocorticoids Androgens Progestins Estrogens Calcitriol (1,25[OH]2-D3) Retinoic acid Thyroid hormones (T3 and T4)

Hormone Metabolism

Mechanism of Action of Group 2 HormonesMechanism of Action of Group 2 Hormones

Effector SystemsEffector Systems

I. Effector systems that produce cytosolicsecond messengerssecond messengers (couple w/ G-protein) for signal transduction

Adenylyl cyclase - cAMP Guanylyl cyclase - cGMP Phospholipase C - phosphoinositides

(DAG & IP3) Calcium - calmodulin (Ca++)

Hormone Metabolism


Effector SystemsEffector Systems

II. Effector system as an intrinsic part of thereceptor

- does not require G-protein to transduce the physiologic action of the ligand

- contains an enzymatic activity within the intracellular domain that phosphorylates tyrosine kinase residues

Mechanism of Action…Mechanism of Action… [Group 2][Group 2]

Mechanism of Action…Mechanism of Action… [Coupling w/ G-protein][Coupling w/ G-protein]



Hormone Metabolism


Adenylate cyclase – cAMP ESAdenylate cyclase – cAMP ES

Regulation through cAMP-dependent protein kinases

Adenylate

cyclase

ATP Mg2+ cAMP (•)

5’-AMPPhosphodiesterase

4 cAMP

C

RR

C

Inactiveprotein kinase

RR•

•

•

• C

Activeproteinkinase

2+Protein

Phosphoproteins

Phosphatase

Physiologic effects

Hormone Metabolism


Adenylate cyclase – cAMP ESAdenylate cyclase – cAMP ES

1. Activators of adenylyl cyclase1. Activators of adenylyl cyclase Cholera toxin – inactivates GTPase;

s is frozen in active form

Pertussis toxin – prevents activation ofi subunit

2. Inhibitor of adenylyl cyclase2. Inhibitor of adenylyl cyclase Phosphodiesterase – hydrolyzes cAMP

to 5’-AMP

Hormone Metabolism


Hormone Action using cAMP Second MessengerHormone Action using cAMP Second Messenger

Glycogen synthase a

Glycogen synthase b

Protein kinase(Inactive)

Protein kinase(Active)

Phosphoproteinphosphatase

Insulin

(+)

(+)(+)

(+)Glycogen

Phosphorylase bGlycogen

Phosphorylase a

Glycogen

Glucose-1-PO4

(+)

GLYCOGENOLYSIS

Phosphorylasekinase (inactive)

Phosphorylasekinase (active)

Phospho-protein

phosphatase

Adenylatecyclase

ATP

cAMP

(+)(-)

(+)

Muscles Liver

Hormone Metabolism


Hormone Action using cAMP Second MessengerHormone Action using cAMP Second Messenger

Specific Protein

or TranscriptionmRNA

TranslationmRNA

Metabolic response cAMP response element (CRE)

Adenylatecyclase

ATP

cAMP

Protein kinase(Inactive)

Protein kinase(Active)

CREB

CREB-P

(+)(-)

(+)

Muscles Liver

Hormone Metabolism


Receptor

DAG

IP3

Ca++

Protein kinase C

Phosphoproteins

Proteins

Physiologic responses

Ca++-Calmodulin

Calmodulin kinases

(+)

(+)GDP GTP

Phospholipase C

GTP GDP

(+)

PIP2

Hormone Action using DAG, IPHormone Action using DAG, IP33 and Ca and Ca++++

as Second Messengersas Second Messengers

Phosphatidylinositol Cycle and CalciumPhosphatidylinositol Cycle and Calcium

Hormone Metabolism


Kinase Cascade System 1 Kinase Cascade System 1 [Autophoshorylation][Autophoshorylation]

(Autophosphorylation)Phosphorylation ofprotein substrates

(Tyrosine)

Cell growthDNA synthesis

Early response genes

Enzyme Activity

Protein Translocation

Gene Expression

P P

ES utilized by Insulin, EGF PDGF and IGF-1ES utilized by Insulin, EGF PDGF and IGF-1

Hormone Metabolism


Kinase Cascade System 2Kinase Cascade System 2

ES utilized by Growth hormone, Prolactin, EPO, cytokines…ES utilized by Growth hormone, Prolactin, EPO, cytokines…

Regulates transcription

Nucleus

Dimerization

X = SHC GRB2 PLC PI-3K GAP

JAK PJAKP

P PP P

STATs

XSH2P

P)(

JAK PJAKP

P PP P

JAK JAK

Hormone Metabolism


Hormones that bind to CM receptorsHormones that bind to CM receptors

2a2a – second messenger is cAMP

2b2b – second messenger is cGMP

2c2c – second messenger is Ca++orphosphoinositols or both

2d2d – second messenger is kinase/phosphatase cascade

Hormone MetabolismHormone Metabolism

Factors Affecting Response ofFactors Affecting Response ofTarget Cells to HormonesTarget Cells to Hormones

concentration of the hormoneconcentration of the hormone number of receptorsnumber of receptors duration of exposureduration of exposure intracellular conditions such as intracellular conditions such as

conc. of rate-limiting enzymes, conc. of rate-limiting enzymes, substrates or cofactorssubstrates or cofactors

antagonistic or synergistic hormonesantagonistic or synergistic hormones

Hormones That AffectHormones That AffectFuel metabolismFuel metabolism

Hormone Metabolism

InsulinInsulin GlucagonGlucagon SomatostatinSomatostatin CatecholaminesCatecholamines Steroid HormonesSteroid Hormones Thyroid HormonesThyroid Hormones Growth HormonesGrowth Hormones

Metabolic Effects of HormonesMetabolic Effects of Hormones

Pathways Insulin Glucagon Epi T3, T4 Cortisol GH

Glycolysis

Glycogenesis

Glycogenolysis

Gluconeogenesis

Lipogenesis

Lipolysis

Protein Synthesis

Pathology

(+) Stimulated; (-) Inhibited(+) Stimulated; (-) Inhibited

(+)(+)

(+)(+)

(+)(+)

(+)(+)

(-)(-)

(-)(-)

(-)(-)

(-)(-)

(-)(-)

(-)(-)

(-)(-)

(+)(+)

(+)(+)

(+)(+)

(+)(+)

(-)(-)

(-)(-)

(-)(-)

(+)(+)

(+)(+)

(+)(+)

(+)(+)

(-)(-)

(-)(-)

(+)(+)

(+)(+)

(+)(+)

(+)(+)

(-)(-)

(+)(+)

(+)(+)

(+)(+)

(-)(-)

(+)(+)

(+)(+)

(-)(-)

(+)(+)

(-)(-)

(++)(++)

(+)(+)

(+)(+)

(+)(+)

““central”central”

““peripheral”peripheral”

““Liver”Liver” ““L & M”L & M”

DM,DM,Lepre-Lepre-chaunismchaunism

GlucagonomaGlucagonomaParkinson’sParkinson’sPheochromo-Pheochromo-cytomacytoma

Grave’s D.Grave’s D.MyxedemaMyxedemaCretinismCretinismGoiterGoiter

Cushing’sCushing’sConn’sConn’sAddison’sAddison’s

DwarfismDwarfismGigantismGigantism

Hormone Metabolism

Insulin …Insulin …

Mechanism of ActionMechanism of Action

Transduction thru tyrosine kinaseTransduction thru tyrosine kinase

Autophosphorylation [-subunit]

(+)/(-) of cytoplasmic proteins

Phosphorylation of proteins

(+) of tyrosine kinase activity

Biologic effects [long term effects]

Hormone Metabolism



Second MessengersSecond Messengers

Release of glycoinositol derivative

(+)/(-) of cytoplasmic proteins

Dephosphorylation of proteins

(+) Phosphoprotein phosphatase

Biologic effects [short term effects]

Hormone Metabolism



Hormone Metabolism


Effects on MetabolismEffects on Metabolism

Enzyme Change in Activity Possible Mechanism

cAMP metabolism Phosphodiesterase (low Km) Increase Phosphorylation Protein kinase (cAMP-dependent) Decrease Association of R

and C subunitsGlycogen metabolism Glycogen synthase Increase Dephosphorylation Phosphorylase kinase Decrease Dephosphorylation Phosphorylase Decrease Dephosphorylation

Glycolysis & Gluconeogenesis Pyruvate dehydrogenase Increase Dephosphorylation Pyruvate kinase Increase Dephosphorylation Phosphofructokinase Increase Dephosphorylation Fructose-2,6-bisphosphatase Decrease Dephosphorylation

Hormone Metabolism


Effects on MetabolismEffects on Metabolism

Enzyme Change in Activity Possible Mechanism

Lipid metabolism Acetyl-CoA carboxylase Increase Dephosphorylation HMG-CoA reductase Increase Dephosphorylation Triacylglycerol lipase Decrease Dephosphorylation

Signaling molecules p42/44MAP kinase Increase Dephosphorylation p90RSK Increase Dephosphorylation GSK3 Decrease Dephosphorylation p70 S6 kinase Increase Dephosphorylation Phosphoprotein phosphatase Increase Dephosphorylation 1G

Hormone Metabolism


PathophysiologyPathophysiology

Diabetes MellitusDiabetes Mellitus

Type 1 – Insulin dependent DM (IDDM)

Type 2 – Non-insulin dependent DM (NIDDM)


Leprechaunism Leprechaunism

[“Donohue’s Syndrome”][“Donohue’s Syndrome”]

Metabolic Syndrome / Insulin Resistance SyndromeMetabolic Syndrome / Insulin Resistance Syndrome

Hormone Metabolism


Syndrome X, Syndrome X, Reaven Syndrome Reaven Syndrome Dysmetabolic S. Dysmetabolic S. The “H” phenomenonThe “H” phenomenon

The “Deadly Quartet”The “Deadly Quartet”

Hormone Metabolism



Somogyi Effect Somogyi Effect [rebound hyperglycemia]

- rapid in blood glucose that generates the release of counterregulatory hormones (Epi, glucagon, cortisol) rapid of glucose

- hypoglycemia results from:1) autonomic neuropathy2) inappropriate timing of insulin3) exercise w/o adequate caloric intake4) excessive insulin treatment

Hormone Metabolism



Dawn Phenomenon Dawn Phenomenon

- early morning (5:00 to 6:00AM) increase in blood glucose associated with the release of nocturnal growth hormone

- 3:00 AM glucose is normal, while 8:00 AM glucose is

Hormone Metabolism



Maillard reaction Maillard reaction

- non-enzymatic glycosylation of proteins due to high blood glucose levels

- sugar aldehyde or ketone group condenses with a free amino group Schiff base Amadori productsAmadori products (stable ketoamines) degrade into reactive carbonyl-containing products react w/ amino groups cross-linkages and adducts DAMAGEDAMAGE

Hormone Metabolism

Catecholamines …Catecholamines …

Synthesis & StructuresSynthesis & Structures

CH2 - C – NH2

HO H

COOH

Tyrosine Dopa

HO

HO

CH2 - C – NH2

H

COOH

Dopamine

HO

HO

CH2 - CH2 – NH2

Norepinephrine

HO

HO

CH - CH2 – NH2

OH

Epinephrine

HO

HO

CH - CH2 – NHCH3

OH

Tyrosine hydroxylaseDopa

decarboxylase

Dopamine-hydroxylase

PNMT


Chromaffin CellChromaffin Cell

TyrosineTyrosine

(+) - adrtenergic & cholinergic agents(-) -adrenergic agents

E

ENE

NE

Tyrosine

Dopa

Dopamine

Granule

E

NE

NE

DBH

TH

DD PNMT

BiosynthesisBiosynthesis

Hormone Metabolism

Hormone Metabolism


Secretion of Stress HormonesSecretion of Stress Hormones

Stress

Hypothalamus

ACTH

Cortisol EP

Blood glucose

Blood

Tyr, PheChromaffin CellChromaffin Cell

EP

EP

Tyrosine

NEPPNMT


MetabolismMetabolism

rapidly metabolized in the liver andskeletal muscles

metabolized by: catechol-O-methyl transferase (COMT)monoamine oxidase (MAO)

free catecholamines may also be inactivated by conjugated with sulfate orglucoronide in the liver

Hormone Metabolism

Hormone Metabolism



act through 2 major classes of receptors:-Adrenergic (1, 2)-Adrenergic (1, 2)

Epinephrine binds and (+) both and R:- much greater affinity with R

Norepinephrine primarily binds with R

Hormone Metabolism

Catecholamines …Catecholamines … Mechanism of ActionMechanism of Action

1, 2 (+) adenylyl cyclase

2 (-) adenylyl cyclase

1 couples to processes that alter Ca++ concentration or modify phosphatidylinositol metabolism or both

Binding of catecholamines to:


Hormone Metabolism


Parkinson’s disease

Pheochromocytoma

Thyroid Hormones …Thyroid Hormones …

Hormone Metabolism


Hypothyroidism/MyxedemaHypothyroidism/Myxedema- T3 and T4; BMR

Hyperthyroidism/ThyrotoxicosisHyperthyroidism/Thyrotoxicosis- T3 and T4; BMR- Grave’s disease

GoiterGoiter- enlarged thyroid gland ; elevated TSH- due to iodine deficiency or excess - defect in any steps in the synthesis

Steroids …Steroids …

Hormone Metabolism

SynthesisSynthesis

Pregnenolone

ProgesteroneCortisol,

Aldosterone ,etc.

Cholesterol

(1) SCC

(2) Oxidation & isomerization

(3) Hydroxylation


Hormone Metabolism

Subcellular comparmentalization of Glucocorticoid biosynthesis

R

ACTH

G AC

Cortisol

CholesterolEster

Cholesterol

Lipase

Pregnenolone

ATP

cAMPProtein kinase A

Cholesterol

Cortisol

Progesterone

11-Deoxycortisol

ER

LDL

Steroids …Steroids … Mechanism of ActionMechanism of Action


Hormone Metabolism


Cushing’s syndromeCushing’s syndrome - glucocorticoid excess- due to pharmacologic use of steroids- ACTH-secreting pituitary adenoma or ca.- hyperglycemia or glucose intolerance; truncal obesity; severe CHON metabolism

Conn’s syndromeConn’s syndrome- primary aldosteronism- hypertension, hypokalemia, hypernatremia and alkalosis


Hormone Metabolism


Addison’s diseaseAddison’s disease - primary adrenal insufficiency- severe hypoglycemia - decrease BP, decrease GFR, decrease ability to excrete a water load- skin pigmentation

22° Adrenal Insufficiency° Adrenal Insufficiency- deficiency of ACTH from tumors, infarct, or infection- metabolic syndrome w/o hyperpigmentation


Hormone Metabolism

““High level of serum cortisol may High level of serum cortisol may be responsible for stress-induced be responsible for stress-induced memory loss.”memory loss.”

““Physiologic response to stress Physiologic response to stress does not impair the learning aspect does not impair the learning aspect of memory but only the free recall of memory but only the free recall of information.”of information.”

““Elevated glucocorticoid level may Elevated glucocorticoid level may induce impairment in such induce impairment in such stressful conditions as job stressful conditions as job interviews, combat, courtroom interviews, combat, courtroom testimony and examinations.”testimony and examinations.”

[Nature Neuro-science 2000; 3:313-4 (April)][Nature Neuro-science 2000; 3:313-4 (April)]

Growth H. …Growth H. … SecretionSecretion

Growth H. …Growth H. …Mechanism of ActionMechanism of Action

Growth H. …Growth H. …

Hormone Metabolism

Pathophysiology Pathophysiology

GH deficiency dwarfismGH deficiency dwarfism

Laron type dwarfismLaron type dwarfism

PygmiesPygmies

Growth H. …Growth H. … Pathophysiology Pathophysiology

PygmiesPygmies

PygmiesPygmies


GigantismGigantism


AcromegalyAcromegaly

Hormone Metabolism

neuromuscular excitabilityneuromuscular excitability blood coagulationblood coagulation secretory processessecretory processes membrane integrity/plasmamembrane integrity/plasma

membrane transportmembrane transport enzyme regulationenzyme regulation release of hormones and release of hormones and

neurotransmittersneurotransmitters

CalciumCalcium

CalciumCalcium

Ca and phosphate are necessary Ca and phosphate are necessary for bone mineralizationfor bone mineralization 1 kg Ca [human body]1 kg Ca [human body] 99% 99% bone bone (hydroxyapatite)(hydroxyapatite) miscible pool miscible pool (1% of the skeletal (1% of the skeletal muscle Ca and 1% periosteal space)muscle Ca and 1% periosteal space) 7.5-10.5 mg/dl or 1.1-1.3 mmol/L7.5-10.5 mg/dl or 1.1-1.3 mmol/L

Hormone Metabolism

Hormones That AffectHormones That AffectCalcium metabolismCalcium metabolism

Hormone Metabolism

PTHPTH

CalcitriolCalcitriol

CalcitoninCalcitonin

Hormone Metabolism

Parathyroid Hormone [PTH]Parathyroid Hormone [PTH]

84 amino acid peptide84 amino acid peptide regulates plasma Ca++ levelregulates plasma Ca++ level synthesized in the parathyroid glandsynthesized in the parathyroid gland t½t½ = 20 min after proPTH is synthesized = 20 min after proPTH is synthesized metabolized in the parathyroid tissue metabolized in the parathyroid tissue

and liverand liver

Hormone Metabolism

PTH …PTH …

preproPTH preproPTH proPTH proPTH PTH PTH (115 a.a) (115 a.a) (84 a. a.) (84 a. a.)

ERERRibosomeRibosome GAGA

PTH 1-34 (full biologic activity)PTH 1-34 (full biologic activity)

PTH 25-34 (receptor binding)PTH 25-34 (receptor binding)

Hormone Metabolism

Fates of PTHFates of PTH

Transport to a storage poolTransport to a storage pool

DegradationDegradation

Immediate secretionImmediate secretion

Hormone Metabolism

PTH Secretion PTH Secretion

Regulated by plasma Ca++:Regulated by plasma Ca++:

acute acute Ca++ Ca++ PTH mRNA PTH mRNA PTH synthesisPTH synthesis

1,25(OH)2-D3 1,25(OH)2-D3 VDRC/VDHRE VDRC/VDHRE PTH mRNA transcriptionPTH mRNA transcription

(+) G-protein (+) G-protein (+) phospholipase C (+) phospholipase C IP3 IP3 Ca++Ca++ secretion secretion

Hormone Metabolism

PTH MetabolismPTH Metabolism

metabolized in the parathyroid tissuemetabolized in the parathyroid tissue

Cathepsins B and DCathepsins B and D Cathepsins B cleaves:Cathepsins B cleaves:

PTH PTH [1-36 and 37-84] [1-36 and 37-84]

principal site of peripheral proteolysisprincipal site of peripheral proteolysisoccurs in the liver occurs in the liver (Kuppfer cells)(Kuppfer cells)

excretion of metabolites excretion of metabolites (kidneys)(kidneys)

Hormone Metabolism

PTH ActionsPTH Actions

PTHPTH

(+) G-protein(+) G-protein

cAMPcAMP

BONESBONES KIDNEYSKIDNEYS INTESTINESINTESTINES

Hormone Metabolism

PTH ActionsPTH Actions

BONESBONES KIDNEYSKIDNEYS INTESTINESINTESTINES

Direct EffectsDirect Effects Indirect EffectIndirect Effect

Increase bone Increase bone resorptionresorption

Decrease renal Decrease renal Ca++ Ca++ excretionexcretion

Increase Ca++Increase Ca++absorptionabsorption

(CALCITRIOL)(CALCITRIOL)

CALCITRIOLCALCITRIOL

derivative of vitamin Dderivative of vitamin D

regulates plasma Ca++ levelregulates plasma Ca++ level

synthesized in the kidneysynthesized in the kidney

ensures Ca and phosphate for ensures Ca and phosphate for bone mineralizationbone mineralization

Hormone Metabolism

Synthesis of CalcitriolSynthesis of Calcitriol

Hormone Metabolism

7-dehydrocholesterol 7-dehydrocholesterol

25-OH-D325-OH-D3

SKINSKIN

Vit D3 Vit D3

1, 25-(OH)1, 25-(OH)22-D3-D3

LIVERLIVER

KIDNEYKIDNEY [placenta][placenta]

(Photolysis)(Photolysis)

(25-hydroxylase)(25-hydroxylase)

(1-hydroxylase)(1-hydroxylase)


Hormone Metabolism

Nuclear actionNuclear action (+) VDRE(+) VDRE

Induces Ca binding protein (CBP)Induces Ca binding protein (CBP)

Increases transfer of Ca & PO4 acrossIncreases transfer of Ca & PO4 acrossthe intestinal mucosathe intestinal mucosa

When you do not succeed in taking giant steps on the road to your goal,

be satisfied with little steps, and wait patiently till the time that

you are able to run, or better still, to fly.

Be satisfied to be a little bee in the hive who will soon become a big bee

capable of making honey…

Thank you …Thank you …

(Padre Pio)