Principles of Hormonal Integration

PRINCIPLES OF HORMONAL INTEGRATION

INTEGRATION OF HORMONAL SIGNALS AT THE CELLULAR AND MOLECULAR LEVEL
AUGMENTATION, ANTAGONISM AND SYNERGY PERMISSIVENESS MAINTAINING SIGNAL FIDELIT Y

MODULATION OF RESPONDING SYSTEMS

SENSITIVIT Y AND CAPACIT Y SPARE RECEPTORS

HORMONAL INTEGRATION AT THE WHOLE ANIMAL LEVEL

REDUNDANCY REINFORCEMENT PUSH PULL MECHANISMS

INTRODUCTION
Life processes are more complex, and that endocrinological solutions to physiological problems require integration of a large variety of simultaneous events Integration: coordination of reactions to separate physiological demands into a balanced overall response or group of responses

MULTIPLE SIGNALS ARE INTEGRATED

Cell receives multiplicity of signals - excitatory or inhibitory, simultaneously The signals are integrated at receptor and post receptor levels and a collective response emerges

INFLUENCE OF ONE HORMONE ON ANOTHER HORMONE

Through modulation of key components of transduction or signaling pathways. Epinephrine acts via adrenergic receptors Thyroid hormones increases expression of adrenergic receptors Cortisol increases expression of adrenergic receptors, as well as G s, and other components of G -protein signaling In thyroid or adrenal insuf ficiency, responses to epinephrine are blunted or deficient, and conversely, After a period of increased secretion of thyroxine or cortisol, responses to epinephrine may be exaggerated

SYNERGISM, ANTAGONISM, AUGMENTATION

Effect of multiple hormones actin simultaneously are
Greater ( synergism or potentiation )- Separate complementary pathway Equal ( summation ) Independent pathways for same response Lesser ( antagonism ) shared component of their signaling pathways of final effector molecules

Eg: Synergy -Cortisol and Growth hormone on lipolysis

PERMISSIVENESS
A hormone acts permissively when its presence is necessary for, or permits, a response to occur, even though the hormone itself does not initiate the response Eg : Cortisol is indispensable as a permissive agent for the actions of glucagon and catecholamines on gluconeogenesis and glycogenolysis.

MAINTAINING SIGNAL FIDELITY

More hormones than the number of pathways . Different hormones uses shared pathways but delivers unique response
Mechanism: A hormone activates multiple parallel pathways and the specific combination ensures the fidelity Spatial arrangement ensures fidelity ( Signaling proteins are anchored on cytoskeleton or to membrane organelles) Eg: Protein kinase A are anchored by AKAPs (A kinase anchoring proteins) Isoforms have different regulatory unit and cellular loci Eg: Adenylyl cyclase has 9 isoforms All are activated by four different isoforms of G s and 50 combination of G-protein , protein kinase C family, or by calcium.

MODULATION OF RESPONDING SYSTEM

D ete r m in a n t s o f t h e m a g n i t ud e o f h o r m o n al responses A . C o n c e n t r a t i o n o f h o r m o n e a t t h e t a r g et cell sur face 1 . R a te o f s e c r et i on 2 . R a te o f d e l i ve r y b y t h e c i rc ul a t i o n 3 . R a te o f h o r m o n e d e g r a d a t io n B . S e n s i t i v i t y o f t a r g et c e l l s 1 . N u m b e r o f f u n c t i o n a l r e c e p to r s per cell 2 . Re c e p to r a f f i n i t y f o r t h e h o r m o n e 3 . Po s t - r e c e p to r a m p l ifi c a t i o n capacity 4 . A b u n d a n c e o f av a i l a b l e e f f e c to r m o l e c ule s C . N u m b e r o f f u n c t io n a l t a r g et c e l l s D ete r m in a n t s o f t h e d u r a t i o n o f h o r m o n al responses A . D u r a t io n o f h o r m o n e av a i l a b i li t y 1 . D u r a t io n o f s e c r et i o n 2 . A m o un t s e c r ete d 3 . H a l f - l i fe i n b l o o d B . M o d e o f p r o d uc t i o n o f c e l l ula r r e s p o n s e 1 . Rev e r s i b l e c o v al e n t m o d i fi c a t io n s 2. Genomic changes a . T i m e n e e d e d to s y n t h e si z e m R N A b . H a l f - l ife o f m R N A c . T i m e n e e d e d to s y n t h e s i z e p r o te i n s d . H a l f - l ife o f a f f e c te d p r o tei n s C . R a p i d i t y o f o n s et o f c o m p e n s a to r y c h a n g e s 1 . C o u n te r ac t i n g r e s p o n s e s 2 . Re c e p to r d e s e n s i t iz a t io n o r d o w n r e g u l a t io n

SENSITIVITY AND CAPACITY

Sensitivity describes the acuity of the ability of a cell or organ to recognize and respond to a signal in proportion to the intensity of that signal The capacity to respond, or the maximum response that a tissue or organ is capable of achieving depends upon the number of target cells and their competence. Hormones regulate both the sensitivity and the capacity of target tissues to respond either to themselves or to other hormones.

MODULATION OF SENSITIVITY
Modulation of sensitivity by altering the number of receptor s on the cell sur face (down regulation / up regulation). Eg: Insulin in hyperinsulinemia Increase in adrenergic receptor following dener vation and exaggerated response on rener vation for epinephrin A hormone can regulate the number of receptor of other hormone Eg: T3 decreases the sensitivity of the thyrotrope of the pituitar y to TRH Eg: The ovarian hormone progesterone may down-regulate both its own receptor and that of estrogen as well

SPARE RECEPTORS
Af finity reflects the tightness of binding or the likelihood that an encounter between a hormone and its receptor will result in binding, and usually is quantified in terms of the concentrati on of hormone at which half of the available receptor s are occupied by hormone. When fewer than 100% of the receptor s need to be occupied to obtain a maximum response, cells are said to express spare receptor s . For example, glucose uptake by the fat cell is stimulated in a dose -dependent manner by insulin, but the response reaches a maximum when only a small percentage of available receptor s are occupied by insulin . The magnitude of a cellular response to a hormone is determined by summation of the signals generated by each of the occupied receptor s, and therefore is related to the number of receptor s that are activate d rather than the fraction of the total receptor pool that is bound to hormone.

IMPLICATIONS OF SPARE RECEPTORS

Spare receptors may help to internalize for degradation of the hormone Some of such receptor lack the downstream signaling mechanism and functionally committed for hormone degradation, Eg: clearance receptor for (atrial natriuretic factor) Spare receptors thus may blunt potentially harmful over-responses to rapid changes in hormone concentrations and facilitate clearing hormone from blood.

POST-RECEPTOR SENSITIVITY MODULATION

Up- or downregulation of ef fector molecules such as enzymes , ion channels, contractile proteins , and other s may amplify or dampen responses and hence change the relationship between receptor occupancy and magnitude of response Eg: The activity of cAMP phosphodiesterase increases in adipocytes in the absence of pituitar y hormones. It may be recalled that this enzyme catalyzes the degradation of cAMP. When its activity is increased, less cAMP can accumulate af ter stimulation of adenylyl cyclase by a hormone such as epinephrine

CAPABILITY AND NUMBER OF TARGET CELLS

At the tissue, organ, or whole body level, the response to a hormone is the aggregate of the contributions of all the stimulated cells, so that the magnitude of the response is determined both by the number of responsive cells and their competence . For example, ACTH produces a dose -related increase in blood cor tisol concentrati on in normal individuals. However, immediately af ter removal of one adrenal gland, changes in the concentration of cor tisol in response to ACTH administration would be only half as large as seen when both glands are present. Therefore , a much higher dose of ACTH will be needed to achieve the same change as was produced preoperatively. With time however, as the adrenal cor tical cells upregulate ACTH receptor s and increase their enzymatic capacity for steroidogenesis , the concentration of ACTH needed to achieve a par ticular rate of cor tisol secretion will decline.

REDUNDANCY
Duplicative, overlapping control s ensures that the crucial functions are always preser ved Liver glycogen to Blood glucose by epinephrin (adrenal medula) and glucogon (alpha cells of pancreas) Via Increase in cAMP levels activates phosphor yl ase catalyzes glycogenolysi s Two dif ferent hormones from two dif ferent tissues during dif ferent conditions result in same end result Molecular level : Epinephrin can activate phosphor yl ase via stimulating -adrenergic receptor or 1-adrenergic receptor

VARIABILITY IN TIME AND IN PHYSIOLOGY

Redundance provides flexibility. Variation in the physiological function but results in same response. Eg: Increase in blood calcium level is brought by parathyroid hormone by mobilizing bone calcium and increasing the Vitamin D mediated calcium absorption . Variations in time constants

IMPLICATIONS OF REDUNDANCY
Complete failure one mechanism is compensated by increased reliance on other mechanism Example: Knock out of impor tant protein results in no apparent functional changes Functional deficiencies will be masked by redundant mechanisms Conversely, strategies for therapeutic inter ventions designed to increase or decrease the rate of a process must take into account the redundant inputs that regulate that process Merely accelerating or blocking one regulator y input may not produce the desired ef fect since independent adjustments in redundant pathways may completely compensate for the inter vention.

REINFORCEMENT
A hormone may produce radically dif ferent responses at dif ferent locales, which never theless reinforce each other from the perspective of the whole organism. A good example of this is the action of glucocor ticoid hormones to promote gluconeogenesis. Glucocor ticoids promotes protein breakdown in muscle and lymphoid tissues and the consequent release of amino acids into the blood. In adipose tissue glucocor ticoids promote triglyceride lipolysis and the release of glycerol. In the liver, glucocor ticoids induce the formation of the enzymes necessar y to convert amino acids, glycerol, and other substrates into glucose . Complementar y actions increase the overall magnitude and speed of the response.

PUSH-PULL MECHANISMS
Many critical processes are under dual control by agents that act antagonistically either to stimulate or to inhibit. Such dual control allows for more precise regulation through negative feedback than would be possible with a single control system Eg: Hepatic production of glucose, which is increased by glucagon and inhibited by insulin.

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