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Endocrine Endocrine SystemSystem
Huiping Wang (Huiping Wang (王会平王会平 ), PhD), PhD
Department of PhysiologyDepartment of Physiology
Rm C516, Block C, Research Building, School of MedicineRm C516, Block C, Research Building, School of Medicine
Tel: 88208252Tel: 88208252
Email: [email protected]: [email protected]
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RECOMMENDED TEXTBOOK:RECOMMENDED TEXTBOOK: Widmaier EP, Raff H, Strang KT (2006) Widmaier EP, Raff H, Strang KT (2006) Vander’s Human PhysiologyVander’s Human Physiology: The Mechanisms of Body Function, Tenth : The Mechanisms of Body Function, Tenth Edition. McGraw-Hill.Edition. McGraw-Hill.
SUPPLEMENTARY READING:SUPPLEMENTARY READING: Stephan Sanders (2003) Stephan Sanders (2003) Endocrine and Reproductive systemsEndocrine and Reproductive systems, Second Edition. Mosby., Second Edition. Mosby.
COURSE WEBSITERS:COURSE WEBSITERS: http://www.endocrineweb.com/http://www.endocrineweb.com/
http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/index.htmlhttp://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/index.html http://medical.physiology.uab.edu/cardio.htmhttp://medical.physiology.uab.edu/cardio.htm http://www.mhhe.com/biosci/ap/foxhumphys/student/olc/index.htmhttp://www.mhhe.com/biosci/ap/foxhumphys/student/olc/index.htm
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Endocrine Endocrine SystemSystem
General Principles of Endocrine PhysiologyGeneral Principles of Endocrine Physiology
Hypothalamus and pituitary glandHypothalamus and pituitary gland
Thyroid glandThyroid gland
Endocrine Regulation of Calcium and Phosphate Endocrine Regulation of Calcium and Phosphate
MetabolismMetabolism
Adrenal glandAdrenal gland
Pancreatic hormonesPancreatic hormones
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General Principles General Principles
of Endocrine Physiologyof Endocrine Physiology
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OutlineOutline
Endocrine system and Endocrine system and HormoneHormone Hormone types Hormone types Hormone synthesis, storage, release, Hormone synthesis, storage, release,
transport, clearance and action modestransport, clearance and action modes Characteristics of hormonesCharacteristics of hormones Regulation of Hormone SecretionRegulation of Hormone Secretion Mechanisms of hormone actionMechanisms of hormone action
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Endocrine System
One of the two major communication systems in the body Have much longer delays Last for much greater lengths of time
Integrate stimuli and responses to changes in external and internal environment
crucial to coordinated functions of highly differentiated cells, tissues and organs
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Endocrine gland (ductless) is a group of cells that produce and secret a hormone
Endocrine GlandsHypothalamus
Pituitary (Anterior and Posterior)
Thyroid / Parathyroid
Endocrine Pancreas (islets)
Adrenal Cortex and Medulla
Gonad (Ovary and Testis)
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Endocrine System
The endocrine system broadcasts its
hormonal messages to target cells by
secretion into blood and extracellular
fluid. Like a radio broadcast, it requires a
receiver to get the message - in the case
of endocrine messages, cells must bear
a receptor for the hormone being
broadcast in order to respond.
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What is a hormone?What is a hormone?
Chemical Chemical messengermessenger synthesized by specific ensynthesized by specific endocrine cells in response to certain stimuli and sdocrine cells in response to certain stimuli and secreted into the bloodecreted into the blood
Travel via the circulation to affect one or moreTravel via the circulation to affect one or more grgroups of different cellsoups of different cells ( (target cellstarget cells)) to elicit a ph to elicit a physiologicalysiological responseresponse
Hormones are primarily informationHormones are primarily information transferring moleculestransferring molecules
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Types of Hormones
Types Amines Steroids Protein and
peptides
Example T4, T3,T4, T3,
catecholaminecatecholamine
Hormones from Hormones from adrenal cortexadrenal cortex
and gonadsand gonads
Most of hormonesMost of hormones
insulin, oxytocin, insulin, oxytocin, GHGH
Synthesis Tyrosine Cholesterol DNA – mRNA –DNA – mRNA –
Preprohormone -Preprohormone -
ProhormoneProhormone
Feature lipid insolublelipid insoluble lipid solublelipid soluble lipid insolublelipid insoluble
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NUCLEUS
The DNA code is “transcribed” into mRNA.
RIBOSOMES
The mRNA is “translated” to give instructions for proteins synthesis.
Synthesis of peptide hormonesSynthesis of peptide hormones
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Typical synthesis of peptide hormonesTypical synthesis of peptide hormones
PreprohormonesPreprohormones- larger hormones - larger hormones
produced on the ribosomes of the produced on the ribosomes of the
endocrine cellsendocrine cells
ProhormonesProhormones- cleavage of - cleavage of
preprohormones by proteolytic preprohormones by proteolytic
enzymes in rERenzymes in rER
ProhormonesProhormones- packaged into - packaged into
secretory vesicles by the Golgi secretory vesicles by the Golgi
apparatusapparatus
ProhormonesProhormones- cleaved to give - cleaved to give
active hormone and pro-fragmentsactive hormone and pro-fragments
pre-pro-insulin pro-insulin insulin
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Synthesis of steroid hormonesSynthesis of steroid hormones
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Hormone Storage and Release
Thyroid and steroid hormonesThyroid and steroid hormones Not stored as secretory granulesNot stored as secretory granules Transferring through plasma membraneTransferring through plasma membrane
Protein and catecholamine hormonesProtein and catecholamine hormones Stored as secretory granulesStored as secretory granules Released by exocytosisReleased by exocytosis
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Hormones are not secreted at auniform rate
In a pulsatile patternIn a pulsatile pattern
Diurnal (circadian) rhythm:Diurnal (circadian) rhythm: linked to sleep-wake cycles linked to sleep-wake cycles
(cortisol, growth hormone)(cortisol, growth hormone)
Be aware of the pulsatile Be aware of the pulsatile nature and rhythmic nature and rhythmic pattern of hormone pattern of hormone secretion when relating the secretion when relating the serum hormone serum hormone measurements to normal measurements to normal valuesvalues
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Hormones are not secreted at auniform rate
Rhythmic secretionRhythmic secretion
CyclicCyclic
oestrogen, oestrogen,
progesterone, LHprogesterone, LH
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Modes of ActionModes of Action
EndocrineEndocrine – transmission of a – transmission of a signal signal from a classicfrom a classic endocrine cell throughendocrine cell through bloodstream to a distant targetbloodstream to a distant target cellcell e.g. testosterone e.g. testosterone
NeurocrineNeurocrine – hormone is – hormone is released frreleased from a neuron downom a neuron down its axon and then its axon and then travels viatravels via the bloodstream to target the bloodstream to target cellcell
ParacrineParacrine - hormone acts on - hormone acts on adjacenadjacent cellst cells e.g. histamine released at site e.g. histamine released at site of injury to constrict blood vessel of injury to constrict blood vessel walls and stop bleedingwalls and stop bleeding
AutocrineAutocrine – hormone is – hormone is released and released and acts on the cellacts on the cell that secreted it.that secreted it. e.g. e.g. norepinephrine itself inhibits further norepinephrine itself inhibits further release by that cellrelease by that cell in the adrenal mein the adrenal medulla dulla
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A secretion may have several sites of action simultaneously
Example:Example:
NorepinephrineNorepinephrine
- - Autocrine Autocrine action action causes negative causes negative feedback on feedback on secretion. secretion.
- Simultaneously, - Simultaneously, endocrine endocrine action action causes respiration causes respiration rate to increase, rate to increase, peripheral blood peripheral blood vessels to constrict, vessels to constrict, etc.etc.
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Hormone Transport
Peptides and catecholaminePeptides and catecholamine water solublewater soluble dissolve in blooddissolve in blood circulate in blood mainly in free formcirculate in blood mainly in free form
Steroid and thyroid hormonesSteroid and thyroid hormones circulate in blood mainly bound to plasma proteinscirculate in blood mainly bound to plasma proteins the free form is biologically activethe free form is biologically active the greater binding, the longer half-lifethe greater binding, the longer half-life
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Hormone Clearance The half-life of a hormone in bloodThe half-life of a hormone in blood
is the period of time needed for its concentration to be reduced by is the period of time needed for its concentration to be reduced by half.half.
Free: minFree: min Binding: mins, hrs, daysBinding: mins, hrs, days
e.g. T4 (6 days); Insulin (0.006 days)e.g. T4 (6 days); Insulin (0.006 days)
Hormone concentration in blood is determined byHormone concentration in blood is determined by secretion ratesecretion rate clearance rateclearance rate
Ways of ClearanceWays of Clearance target cell uptaketarget cell uptake metabolic degradationmetabolic degradation urinary or biliary excretionurinary or biliary excretion
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The “metabolic fate” of a given hormone molecule in the blood
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CharacteristicsCharacteristics of H of Hormoneormoness
Regulates Regulates rate of reactionrate of reaction
Do notDo not initiate initiate
Very specificVery specific
Amplification effectAmplification effect
Present in very small quantityPresent in very small quantity
pg/mL ~ pg/mL ~ g/mLg/mL
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CharacteristicsCharacteristics of H of Hormoneormoness
Interaction between hormonesInteraction between hormones Synergistic actionSynergistic action
Antagonistic actionAntagonistic action
Permissive actionPermissive action Hormone A must be present for the Hormone A must be present for the
full strength of hormone B’s effect.full strength of hormone B’s effect.
Up-regulation of one hormone’s Up-regulation of one hormone’s
receptors by another hormonereceptors by another hormone
the facilitation of the action of one the facilitation of the action of one
hormone by anotherhormone by another
e.g. the ability of TH to “permit” epinephrine-induced e.g. the ability of TH to “permit” epinephrine-induced release of fatty acids from adipose tissue cells (TH release of fatty acids from adipose tissue cells (TH causes an causes an no. of epinephrine receptors on the cell) no. of epinephrine receptors on the cell)
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Three types of inputs to endocrine cells that stimulate or inhibit hormone secretion.
Regulation of Hormone Secretion
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Regulation of Hormone Secretion
Negative feedbackNegative feedback Most commonMost common Occurs when a hormone Occurs when a hormone
produces a biologic effect produces a biologic effect that, on attaining sufficient that, on attaining sufficient magnitude, inhibits further magnitude, inhibits further secretionsecretion
Positive feedbackPositive feedback Less commonLess common Amplify the initial biological Amplify the initial biological
effect of the hormoneeffect of the hormone
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Negative FeedbackNegative Feedback
Characteristic of control systems in which system’s Characteristic of control systems in which system’s
response opposes the original change in the system.response opposes the original change in the system.
Hormone Hormone itselfitself feeds back to inhibit its own synthesis.feeds back to inhibit its own synthesis.
Regulated product Regulated product ((metabolite)metabolite) feeds back to inhibit feeds back to inhibit
hormone synthesis.hormone synthesis.
Important for homeostatic control.Important for homeostatic control.
Example: Control of blood glucose by insulinExample: Control of blood glucose by insulin
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Positive FeedbackPositive Feedback
Characteristic of control systems in which an iCharacteristic of control systems in which an i
nitial disturbance sets off train of events that nitial disturbance sets off train of events that ii
ncreases the disturbance even furtherncreases the disturbance even further..
AmplifiesAmplifies the deviation from the normal levels the deviation from the normal levels Example: Oxytocin (suckling)Example: Oxytocin (suckling)
Important for amplification of level for actionImportant for amplification of level for action
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Hormone action mediated by the specific receptors Most hormones circulate in blood, coming into contact with
essentially all cells. However, a given hormone usually affects only a limited number of cells, which are called target cells. A target cell responds to a hormone because it bears receptors for the hormone.
Mechanisms of hormone actionsMechanisms of hormone actions
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Hormone Receptors
Structure Recognition domain binds hormone Coupling domain generates signal
Location cell membrane (e.g. for insulin) cytoplasm (for steroids) nucleus (e.g. for thyroid hormone)
Receptor capacity exposure to excess hormone down-regulates capacity low hormone concentration up-regulates capacity
The receptor provides link between a specific extracellular hormoneand the activation of a specific signal-transduction system
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Two general mechanisms ofhormone action
Second messengers – enzyme activity
↑↓(rapid, cytosolic effects)
Gene expression - enzymes synthesis
↑↓(slow, nuclear effects)
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Mechanisms of Peptide Hormone ActionMechanisms of Peptide Hormone Action
G proteins are GTP-binding proteins couple hormone receptors to adjacent effector molecule have intrinsic GTPase activity have three subunits: α, β, γ α subunit bound to GDP → inactive G protein α subunit bound to GTP → active G protein the effect can be either stimulatory (Gs) or inhibitory (Gi)
Second messengers cAMP second message system IP3 mechanism Ca2+-calmodulin mechanism
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Signal transduction pathway involving adenylate cyclase
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Cyclic AMP signaling-sequence of eventsCyclic AMP signaling-sequence of events
The The hormonehormone ( (11stst messenger messenger) binds to the membrane receptor; the ) binds to the membrane receptor; the membrane receptor changes shape and bind to G protein (GTP-membrane receptor changes shape and bind to G protein (GTP-binding protein)binding protein)
G protein is activated; binds to GTP (Guanosine 5’- triphosphate) and G protein is activated; binds to GTP (Guanosine 5’- triphosphate) and release GDPrelease GDP
Activated G protein moves to membrane and binds and activates Activated G protein moves to membrane and binds and activates adenylate cyclase (GTP is hydrolysed by GTPase activity of G protein)adenylate cyclase (GTP is hydrolysed by GTPase activity of G protein)
Activated adenylate cyclase converts Activated adenylate cyclase converts ATP to cAMP (ATP to cAMP (second second messengermessenger) ) (if inhibited, no catalysed reaction by AC)(if inhibited, no catalysed reaction by AC)
cAMP is free to circulate inside the cell; triggers activation of one to cAMP is free to circulate inside the cell; triggers activation of one to several protein kinase molecules; protein kinase phosphorylates many several protein kinase molecules; protein kinase phosphorylates many proteinsproteins
The phosphorylated proteins may either be activated or inhibited by The phosphorylated proteins may either be activated or inhibited by phosphorylationphosphorylation
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Adenylyl cyclase forms cAMP,a “second messenger” that activates enzymes used in cellular responses.
The phosphodiesterase enzymes “terminate” thesecond messenger cAMP.
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The cAMP system rapidly amplifies the responsecapacity of cells: here, one “first messenger” ledto the formation of one million product molecules.
Amplification effect
Each protein kinase can catalyse hundreds of reactions
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This receptor-G-protein complex is linked to and activates phospholipase C, leading to an increase in IP3 and DAG, which work together to activate enzymes and to increase intracellular calcium levels.
PIP-calcium signaling mechanism
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A hormone A hormone (first messenger)(first messenger) binding to its receptor causes the receptor to binding to its receptor causes the receptor to bind inactive G proteinbind inactive G protein
G protein G protein is activated; binds GTP & releases GDPis activated; binds GTP & releases GDP Activated G protein binds & activates a membrane-bound phospholipase Activated G protein binds & activates a membrane-bound phospholipase
enzyme;enzyme; G protein becomes inactiveG protein becomes inactive
Phospholipase splits Phospholipase splits phosphatidyl inositol biphosphate phosphatidyl inositol biphosphate (PIP(PIP22) to) to
diacylglycerol diacylglycerol (DAG)(DAG) & & inositol triphosphate inositol triphosphate (IP3);(IP3); DAG DAG activates protein kinases on the plasma membrane; activates protein kinases on the plasma membrane; IP3 IP3 triggers triggers calcium calcium
ionion release from the ER release from the ER Released Released calcium ionscalcium ions (second messengers)(second messengers) alter activity specific enzymes’ alter activity specific enzymes’
activity and ion channels or bind to the regulatory protein calmodulin;activity and ion channels or bind to the regulatory protein calmodulin; Calmodulin Calmodulin also activates specific enzymes to amplify the cellular responsealso activates specific enzymes to amplify the cellular response
PIP-calcium signaling mechanism
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Ca-calmodulin system Ca-calmodulin system
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Mechanisms of steroid Hormone ActionMechanisms of steroid Hormone Action
Modulation of gene
expression Steroid hormones bind to
intracellular receptors
The steroid-receptor complex
binds to DNA, turning specific
genes on or off
Steroid hormone receptorSteroid hormone receptor
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Sequence of events for steroid hormone binding
Steroids are lipid-based and can diffuse into cells easilySteroids are lipid-based and can diffuse into cells easily No need for intracellular second messengerNo need for intracellular second messenger Mobile receptorsMobile receptors Some steroids bind to a cytoplasmic receptor, which then Some steroids bind to a cytoplasmic receptor, which then
translocates to the nucleustranslocates to the nucleus Other receptors for steroids are located in the nucleus or are Other receptors for steroids are located in the nucleus or are
nuclear receptor proteins nuclear receptor proteins In both cases, the steroid-receptor complex formed can then bind In both cases, the steroid-receptor complex formed can then bind
to specific regions of DNA and activate specific genes to specific regions of DNA and activate specific genes Activated genes transcribe into messenger RNA and instruct the Activated genes transcribe into messenger RNA and instruct the
cell to synthesize specific enzyme proteins that change the cell to synthesize specific enzyme proteins that change the metabolism of the target cell metabolism of the target cell
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Radioimmunoassay (RIA)
(from the Nobel lecture by Dr. Rosalyn Yalow, 1977)(from the Nobel lecture by Dr. Rosalyn Yalow, 1977)
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The main difference between the modes of action of The main difference between the modes of action of peptide hormones and steroid hormones is thatpeptide hormones and steroid hormones is that
a. peptide hormones bind to intracellular receptors whereas steroid a. peptide hormones bind to intracellular receptors whereas steroid hormones bind to receptors on the cell surface.hormones bind to receptors on the cell surface.
b. peptide hormones bind to receptors in the nucleus whereas steroid b. peptide hormones bind to receptors in the nucleus whereas steroid hormones bind to receptors in the cytosol.hormones bind to receptors in the cytosol.
c. peptide hormones bind to receptors on the cell surface whereas c. peptide hormones bind to receptors on the cell surface whereas steroid hormones act as second messengers.steroid hormones act as second messengers.
d. peptide hormones bind to receptors on the cell surface whereas d. peptide hormones bind to receptors on the cell surface whereas steroid hormones bind to intracellular receptors.steroid hormones bind to intracellular receptors.
e. there are no differences; both act by binding to receptors on the cell e. there are no differences; both act by binding to receptors on the cell surface.surface.
QUIZ
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The main difference between the modes of action of The main difference between the modes of action of peptide hormones and steroid hormones is thatpeptide hormones and steroid hormones is that
a. peptide hormones bind to intracellular receptors whereas steroid a. peptide hormones bind to intracellular receptors whereas steroid hormones bind to receptors on the cell surface.hormones bind to receptors on the cell surface.
b. peptide hormones bind to receptors in the nucleus whereas steroid b. peptide hormones bind to receptors in the nucleus whereas steroid hormones bind to receptors in the cytosol.hormones bind to receptors in the cytosol.
c. peptide hormones bind to receptors on the cell surface whereas c. peptide hormones bind to receptors on the cell surface whereas steroid hormones act as second messengers.steroid hormones act as second messengers.
d. peptide hormones bind to receptors on the cell surface whereas d. peptide hormones bind to receptors on the cell surface whereas steroid hormones bind to intracellular receptors.steroid hormones bind to intracellular receptors.
e. there are no differences; both act by binding to receptors on the cell e. there are no differences; both act by binding to receptors on the cell surface.surface.
QUIZ
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In the absence of thyroid hormone, epinephrine stimulates release of a small In the absence of thyroid hormone, epinephrine stimulates release of a small amount of fatty acids from adipose cells. In the presence of thyroid hormone amount of fatty acids from adipose cells. In the presence of thyroid hormone (which has no effect by itself), epinephrine causes a much more substantial (which has no effect by itself), epinephrine causes a much more substantial release of fatty acids from the cells. The effect of thyroid hormone on release of fatty acids from the cells. The effect of thyroid hormone on epinephrine's actions is calledepinephrine's actions is called
a. antagonistic.a. antagonistic.
b. agonistic.b. agonistic.
c. permissive.c. permissive.
d. direct.d. direct.
e. paracrine.e. paracrine.
QUIZ
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In the absence of thyroid hormone, epinephrine stimulates release of a small In the absence of thyroid hormone, epinephrine stimulates release of a small amount of fatty acids from adipose cells. In the presence of thyroid hormone amount of fatty acids from adipose cells. In the presence of thyroid hormone (which has no effect by itself), epinephrine causes a much more substantial (which has no effect by itself), epinephrine causes a much more substantial release of fatty acids from the cells. The effect of thyroid hormone on release of fatty acids from the cells. The effect of thyroid hormone on epinephrine's actions is calledepinephrine's actions is called
a. antagonistic.a. antagonistic.
b. agonistic.b. agonistic.
c. permissive.c. permissive.
d. direct.d. direct.
e. paracrine.e. paracrine.
QUIZ
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SummarySummary HormoneHormone
Primarily information transferring moleculesPrimarily information transferring molecules Transfer information from one set of cells to anotherTransfer information from one set of cells to another Travel via the circulation to affect one or more groups of different cells to Travel via the circulation to affect one or more groups of different cells to
elicit a physiological responseelicit a physiological response
Hormone typesHormone types Protein and peptides Protein and peptides AminesAmines SteroidsSteroids
Action modes of hormonesAction modes of hormones Endocrine Paracrine Autocrine Neurocrine
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SummarySummary
Regulation of Hormone SecretionRegulation of Hormone Secretion Negative feedbackNegative feedback Positive feedbackPositive feedback
Mechanisms of hormone actionMechanisms of hormone action Mechanisms of Peptide Hormone ActionMechanisms of Peptide Hormone Action
Second messenger signaling pathwaySecond messenger signaling pathway cAMP second message systemcAMP second message system
IPIP33 mechanism mechanism
CaCa2+2+-calmodulin mechanism-calmodulin mechanism
Mechanisms of Steroid Hormone ActionMechanisms of Steroid Hormone Action Modification of gene expressionModification of gene expression