Hormonal Integration

7/28/2019 Hormonal Integration

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Principles of HormonalIntegration



INTEGRATION OF HORMONAL SIGNALS AT THECELLULAR AND MOLECULAR LEVEL

AUGMENTATION, ANTAGONISM AND SYNERGY

PERMISSIVENESS

MAINTAINING SIGNAL FIDELIT Y

MODULATION OF RESPONDING SYSTEMSSENSITIVITY AND CAPACITY

SPARE RECEPTORS

HORMONAL INTEGRATION AT THE WHOLE ANIMAL LEVELREDUNDANCY

REINFORCEMENT

PUSH – PULL MECHANISMS

PRINCIPLES OF HORMONAL INTEGRATION









Effect of multiple hormonesactin simultaneously are

Greater ( synergism orpotentiation )- Separatecomplementary pathwayEqual ( summation ) –

Independent pathways for sameresponseLesser ( antagonism ) -

shared component of theirsignaling pathways of finaleffector molecules

Eg: Synergy - Cortisol andGrowth hormone on lipolysis

SYNERGISM, ANTAGONISM,AUGMENTATION



A hormone acts permissively when its presence isnecessary for, or permits, a response to occur , even thoughthe hormone itself does not initiate the response

Eg : Cortisol is indispensable as a permissive agent for theactions of glucagon and catecholamines ongluconeogenesis and glycogenolysis .

PERMISSIVENESS



More hormones than the number of pathways .Different hormones uses shared pathways but delivers uniquresponseMechanism: A hormone activates multiple parall el pathways andthe specific combination ensures the fidelitySpatial arrangement ensures fidelity ( Signaling proteins are

anchored on cytoskeleton or to membrane organelles)Eg: Protein kinase A are anchored by AKAPs (A kinase anchoringproteins)Isoforms have different regulatory unit and cellular lociEg: Adenylyl cyclase has 9 isoformsAll are activated by four different isoforms of G α s and 50

combination of G-protein β γ , protein kinase C famil y, or bycalcium.

MAINTAINING SIGNAL FIDELITY



MODULATION OF RESPONDINGSYSTEM

Dete rminan t s o f the magn i tude ofhormona lre sponsesA. Conc en t ra t ion o f ho rmone a t the t a rge tc e l l s u r f a c e

1 . R a t e o f s ec re t ion2 . Ra te o f de l ive ry by the c i rcu la t ion3 . Ra te o f ho rmone degrada t ion

B . Sens i t iv i ty o f t a rge t ce l l s1 . Number o f func t iona l recep to rsp e r c e l l2 . Recep to r a ff in i ty fo r the hormone3 . Pos t - recep to r ampl i f i ca t ioncapac i ty4 . Abundance o f ava i l ab le e ffec to r

molecu le sC . Number of func t iona l t a rge t c e l l s

De te rminan t s o f the dura t ion of hormoresponsesA. Dur a t ion o f ho rmone ava i l ab i l i ty

1 . Dura t ion o f sec re t ion2 . Amount sec re ted3 . Ha l f - l i f e in b lood

B. Mode o f p roduc t ion o f ce l lu la r re sponse1 . Reve rs ib le cova len t mod i f i ca t ions2 . Genomic changes

a . Time needed to syn thes izeb . Ha l f - l i f e o f mRNAc. Time needed to syn thes izepro te insd . Ha l f - l i f e o f a ffec ted p ro te inC . Rap id i ty o f onse t o f

compensa to ry c h a n g e s1 . Coun te rac t ing re sponses2 . Recep to r desens i t i za t ion or downregu la t ion



Sensitivity describes the acuity ofthe ability of a cell or organ torecognize and respond to a signalin proportion to the intensity ofthat signal

The capacity to respond, or themaximum response that a tissueor organ is capable of achievingdepends upon the number oftarget cells and their competence .

Hormones regulate both thesensitivity and the capacity oftarget tissues to respond either tothemselves or to other hormones.

SENSITIVITY AND CAPACITY



Modulat ion of sensi t iv i ty by a l ter ing the numberof receptors on the cel l sur face (downregulat ion / up regulat ion) .

Eg: Insul in in hyper insul inemia

Increase in adrenergic receptor fo l lowingdenervat ion and exaggerated response on

renervat ion for epinephr inA hormone can regulate the number of receptorof other hormone

Eg: T3 decreases the sensi t iv i ty of thethyrot rope of the p i tu i tary to TRH

Eg: The ovar ian hormone progesterone may

down-regulate both i t s own receptor and that ofest rogen as wel l

MODULATION OF SENSITIVITY



Aff ini ty ref lects the “ t ightness ” of b inding or the l ikel ihood that anencounter between a hormone and i t s receptor wi l l resul t in b inding, andusual ly i s quant i f ied in terms of the concentra t ion of hormone a t whichhal f of the avai lable receptors are occupied by hormone.

When fewer than 100% of the receptors need to be occupied to obta in amaximum response, cel l s are sa id to express “ spare receptors . ” Forexample , glucose uptake by the fa t ce l l i s s t imulated in a dose-dependentmanner by insul in , but the response reaches a maximum when only a spercentage of avai lable receptors are occupied by insul in .

The magni tude of a cel lu lar response to a hormone is determined bysummat ion of the s ignals generated by each of the occupied receptors , andtherefore i s re la ted to the number of receptors tha t a re ac t iva ted ra thethan the fraction of the total receptor pool that i s bound to hormone.

SPARE RECEPTORS



Spare receptors may help tointernalize for degradation of thehormoneSome of such receptor lack thedownstream signaling mechanismand functionally committed for

hormone degradation, Eg: clearancereceptor for (atrial natriuretic factor)Spare receptors thus may bluntpotentially harmful over-responsesto rapid changes in hormoneconcentrations and facilitate

clearing hormone from blood.

IMPLICATIONS OF SPARE RECEPTORS



Up- or downregulat ion of effector molecules such as enzymes , ionchannels , cont ract i le prote ins , and others may ampl i fy or dampenresponses and hence change the re la t ionship between receptor occupancyand magni tude of response

Eg: The act iv i ty of cAMP phosphodiesterase increases in adipocytes in theabsence of p i tu i tary hormones. I t may be recal led that th is enzymecatalyzes the degradat ion of cAMP. When i t s act iv i ty i s increased, lesscAMP can accumulate af ter s t imulat ion of adenylyl cyclase by a hormonesuch as epinephr ine

POST-RECEPTOR SENSITIVITYMODULATION





Dupl icat ive , over lapping controls ensuresthat the crucia l funct ions are a lwayspreservedLiver g lycogen to Blood glucose byepinephr in (adrenal medula) andglucogon (a lpha cel l s of pancreas)Via Increase in cAMP levels act ivates

phosphorylase cata lyzes g lycogenolysisTwo di fferent hormones f rom twodifferent t i ssues dur ing di fferentcondi t ions resul t in same end resul tMolecular level : Epinephr in can act ivatephosphorylase v ia s t imulat ing

β -adrenergic receptoror

α 1-adrenergic receptor

REDUNDANCY



Redundance provides flexibil i ty.Variat ion in the physiologicalfunction but

resul ts in same response.Eg: Increase in blood calciumlevel is

brought by parathyroid hormone bymobil izing bone calcium andincreas ing theVitamin D mediated calciumabsorpt ion .

Variat ions in t ime constants

VARIABILITY IN TIME AND INPHYSIOLOGY





REINFORCEMENT

A hormone may produce radically different responses at d i fferentlocales , which nevertheless reinforce each o ther f rom theperspect ive of the whole organism.

A good example of this is the ac tion of glucocort icoid hormones topromote gluconeogenesis .

Glucocort icoids promotes protein breakdown in muscle andlymphoid t i ssues and the consequent re lease of amino acids intothe blood. In adipose t issue glucocor t icoids promote triglyceridelipolysis and the relea se of glycerol . In the l iver , glucocort icoidsinduce the format ion of the enzymes necessary to convert aminoacids, glycerol , and other substra tes into glucose .

Complementary act ions increase the overal l magni tude and speedof the response.



PUSH-PULL MECHANISMS

Many cri t ical processes are under dualcontrol by agents that actantagonist ical ly either to s t imu late or toinhibit . Such dual contr ol al lows for moreprecise regulat ion through negat ivefeedback than would be possible with a

single control systemEg: Hepatic production of glucose, whichis increased by glucagon and inhibited byinsulin .

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Hormonal Integration