17. Hormones& Signal Transduction

8/21/2019 17. Hormones& Signal Transduction

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HORMONES

iferent mechanisms involved in hormone action. (MGR U)

ormones are classifed into two broad groups based on the mechanism o action:

roup hormones!

These hormones bind to intracellular receptors to orm receptor hormone complexes (the

intracellular messengers) e.g. estrogens, androgens, glucocorticoids, calcitriol.

roup ll hormones !

These hormones bind to cell surace (plasmam embrane) receptors and stimulate the release o

certain molecules, namely the second messengers which, in turn, perorm the biochemical

unctions. The hormones themselves are the frst messengers. roup ll hormones are subdivided

into three categories based on the chemical nature o the second messengers.

(a) c!"# e.g. !TH, $%H, &H, #TH, glucagon, calcitonin.

(b) #hosphatidyl inositol ' calcium e.g. TH, nH, gastrin, *.

(c) +nnown e.g. growth hormone, insulin, oxytocin, prolactin.

roup hormones!

-. These hormones are lipophilic in nature and can easily pass across the plasma membrane. g.

steroid hormones and thyroid hormones

/. They di0use through the plasma

membrane and bind to the receptors

in the cytoplasm and lead to the

hormone receptor (H) complex in

the cytoplasm.

1. The complex is then

translocated to the nucleus. 2n the

nucleus, the H binds to the specifcregions on the 34! called hormone

response elements (H) and causes

increased expression o specifc

genes

5. Hormone receptor complex with H

promotes initiation and elongation

and termination o 4! synthesis

(transcription).

6. The ultimate outcome is the production

o specifc proteins(translation) in response to hormonal

action.

7. xamples o the e0ect o hormones

on genes are:

a. The induction o synthesis o amino transerases by glucocorticoids.

b. %ynthesis o calcium binding protein by calcitriol

roup hormones!

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-. "any hormones are water8soluble, have no transport proteins (and thereore have a short plasma

hal8lie), and initiate a response by binding to a receptor located in the plasma membrane.

/. The mechanism o action o this group o hormones are mediated by the intracellular signals

generated by c!"#, c"#, a/9 , and phosphatidylinositides. These are called second messengers

and act by a0ecting gene transcription. c!"# is a nucleotide derived rom !T# through the action

o adenylyl cyclase c"#, a nucleotide ormed by guanylyl cyclase c!"# acts as a second

messenger or a ma;ority o polypeptide hormones.

1. The hormone is not passed through the membrane but only the signal is passed hence this

mechanism is called signal transduction

5. roup 22 hormones act frst by binding to a receptor located in the plasma membrane. eceptors,

which have guanine nucleotide, are nown as protein,6>8cyclic !"#), and phosphodiesterase hydrolyses c!"# to

6> !"#

6. yclic !"#, being the second messenger, in turn, activates the en?yme, #*! (yclic !"# dependent

protein inase). yclic !"# binds to the regulatory subunits o #*! so that the catalytic subunitshaving inase activity can phosphorylate proteins (the transer o the phosphate o !T# to a serine

or threonine residue in a variety o proteins). $or eg.

a. %erine !"# which is the inactive orm.

$clic GM%!

A. 2t is made rom T# by the en?yme guanylyl cyclase. ! amily o peptides produced in cardiac atrial

tissues, called atrial natriuretic pepdides, bind and activate the membrane8bound orm o guanylyl

cyclase. This causes natriuresis, diuresis, and inhibition o aldosterone secretion.

B. The increased c"# activates c"#8dependent protein inase (#*), which in turn phosphorylates

a number o smooth muscle proteins leading to relaxation o smooth muscle and vasodilation.

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#alcium!

-. alcium is

also an

intracellular messenger o hormone

action. alcium is an important intracellular regulator o cell unction lie contraction o muscles,

secretion o hormones and neurotransmitters, cell division and regulation o gene regulation.

/. The calcium8dependent regulatory protein is called calmodulin which has our a/9 binding sites,

and ull occupancy o these sites leads to a mared conormational change, which allows calmodulin

to activate en?ymes and ion channels. The interaction o a/9 with calmodulin is similar to the

binding o c!"# to #*! and the subseCuent activation o this molecule.1. %teps:

a. roup 22 hormones lie antidiuretic hormone, and a8- 8type catecholamines act by binding

to membrane surace receptors and activate phospholipase .

b. #hospholipase cataly?es the hydrolysis o phosphatidylinositol 5,68bisphosphate to inositol

trisphosphate (2#1 ) and -,/8diacylglycerol.

c. 3iacylglycerol activates protein inase (#*), and releases o a/9 rom the endoplasmic

reticulum.

d. 2ncrease in intracellular calcium concentration avors ormation o the calmodulin8calcium

complex.

e. The calmodulin8calcium complex binds to inactive en?ymes and results in their conversion to

active en?ymes. g. !denyl cyclase, calcium8dependent protein inases, calcium8

magnesium8!T#ase, cyclic nucleotide phosphodiesterase, nitric oxide synthase and

phosphorylase inase.

hosphatid$linositol phosphates!

a. The binding o some roup 22 hormones to cell surace receptor triggers the activation o the

en?yme phospholipase8 which hydrolyses the phosphatidyl inositol to 2nositol triphosphate (2T#)

and diacylglycerol (3!). These act as second messengers. This is ound in case o vasopressin,

TH, nH, etc.

a. 2#1 can release a99 rom intracellular stores, such as rom endoplasmic reticulum and rom

sarcoplasmic reticulum. The elevated intracellular calcium then triggers processes lie smooth

muscle contraction, glycogen breadown and exocytosis. 3iacylglycerol is capable o activating

protein inase that release a/ rom endoplasmic reticulum.

G&%RO'ENS (Short notes)

-. proteins are intracellular signaling proteins. They are so named because o their ability to bind to

uanosine triphosphate (T# ).

/. proteins are regulated based on their binding to T#.

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1. They also possess T#ase activity, the ability to hydroly?e T# to 3#.

5. Two categories o proteins are nown:

a. Heterotrimeric proteins (heteromericD containing di0erent types o sub units)

b. The as superamily o monomeric proteins

Heterotrimeric G proteins Ras super"amil$ G proteins

Three subunits, =, E, F "onomers

+se 8protein lined receptors +se catalytic receptors

egulate second messengers

as superamily (!%D abbreviation o >at sarcoma>) members are called Gsmall proteins since

they are monomers that resemble ;ust one subunit o the heterotrimeric proteins. The as signaling

involves induction o cell prolieration, cell di0erentiation, or vesicle transport.

. Heterotrimeric G proteins!

tructure!

-. "any hormones and neurotransmitters have receptors on their target cells that are lined to

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5. The T#8bound = subunit o protein, dissociates rom the E and F subunits and activates

adenylate cyclase. The active 8alpha,6>8cyclic !"#).

unctions!

-. c!"# is the intracellular second messenger or several hormones that regulate uel metabolism.

yclic !"# activates the en?yme, #*! (yclic !"# dependent protein inase).

/. yclic !"# binds to protein inase !, which then cataly?es the transer o phosphate rom !T# to

serine, threonine residues o e0ector proteins.

1. %erine

!"# which is the inactive orm. a0eine and theophylline can inhibit phoshodiestrase and enhance the

evel o c!"#

-DRENO#OR'#, HORMONES

. #lassi0cation o" adrenocortical hormones!

a. orticosteroids:

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i. lucocorticoids: example, cortisol rom adrenal cortex.

ii. "ineralocorticoids: example, aldosterone rom adrenal

cortex.

b. %ex hormones:

i. !ndrogens: ex. Testosterone rom testes.

ii. strogens, and progestinJs: example estrogens and progestins

rom ovaries and placenta.

%ynthesis o steroid hormones:

a. holesterol is the precursor o all classes o steroid hormones.

b. holesterol is frst acted upon by desmolase and a 78carbon unit is cleaved o0, orming the /-

carbon steroid, pregnenolone. 2t is a common precursor or all the steroid hormones.

c. !TH stimulates this step. This is the rate limiting step or synthesis o all steroid hormones.

d. #

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s

t

e

r

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e

is

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frst steroid hormone ormed rom pregnenolone in two steps. The beta hydroxyl group is

converted to a eto group by a 18beta8ol8dehydrogenase and the K6 double bond shited to K5.

e. #rogesterone is urther converted into:

i. lucocorticoids

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ii. "ineralocorticoids

iii. %ex streroids

*UN#'ONS O* -DRENO#OR'#-, HORMONES

. Role o" adrenocortical hormones in protein meta1olism %on Ma$ 223

. *unctions o" adrenal cortical hormones. MGR U

. *unctions o" Glucocorticoids. MGR U

. 6hat is the mechanism o" action o" steroid hormones7 MGR U

. -ddison9s disease.

O#HEM#-, *UN#'ONS O* -DRENO#OR'#OS'ERODS!

lucocorticoid hormones:

-. The important glucocorticoids are8cortisol, cortisone and corticosterone.

/. #ar1oh$drate meta1olism:

a. 2ncrease blood glucose concentration and produce hyperglycemia

1. Mechanism o" h$perl$caemia!

i. 3ecreases glucose uptae and utilisation in muscles, in adipocytes and lymphoid cells

by inhibiting the membrane transport o glucose into these cells.

ii. nhancing gluconeogenesis in liver.

iii. 2nduces the synthesis o ey gluconeogenic en?ymes such as pyruvate carboxylase,

## carboxyinase, ructose -878bi8phosphatase and also lucose8 78phosphatase.

iv. 2t maes available more o substrates reCuired or gluconeogenesis. This is achieved

by:

a. 2ncreasing protein catabolism in extrahepatic tissues.

b. 3ecreasing incorporation o amino acids in protein in peripheral tissues.

c. !lso increasing synthesis o some ey en?ymes reCuired or amino acidcatabolism lie, alanine transaminase, tyrosine transaminase, tryptophan

pyrrolase, etc.

v. 3ecreases glycolysis in peripheral tissues:

c. 2n liver: lucocorticoids are anabolic. 2t increases the glycogen store in liver. This is due to:

i. 2ncrease in gluconeogenesis rom amino acids and glycerol.

ii. 2ncrease in the synthesis o phosphoenolpyruvate carboxyinase, the rate limiting

en?yme in gluconeogenesis.

d. The biological actions o glucocorticoids generally oppose that o insulin.

1. ,ipid meta1olism :

a. 2ncrease the circulating ree atty acids by:i. 2ncreased breadown o storage triacylglycerol ( ipolysis) in adipose tissue.

ii. educed utili?ation o plasma ree atty acids or the synthesis o triacylglycerols.

5. Efects on protein meta1olism: (%.4)

a. lucocortiocoids exhibit both catabolic and anabolic e0ects on protein and nucleic acid

metabolism.

b. !nabolic e0ects:

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i. 2n liver: ortisol is anabolic, it increases protein synthesis.They promote transcription

(4! synthesis) and protein biosynthesis (translation) in liver.

ii. These anabolic e0ects are caused by the stimulation o specifc genes.

iii. 2t increases hepatic uptae o amino acids.

iv. 2ncorporation o amino acids into ribosomal proteins.

v. 2ncreased m84! ormation and synthesis o proteins including plasma proteins.

vi. 2n liver, cortisol also enhances urea synthesis rom amino acids. There is increased

synthesis o en?ymes necessary or urea cycle, e.g. arginino succinate synthetase,

arginase, etc.

c. atabolic e0ects:

i. lucocorticoids (particularly at high concentration) cause catabolic e0ects in

extrahepatic tissues (e.g. muscle, adipose tissue, bone etc.). This results in enhanced

degradation o proteins.

ii. 2n peripheral extrahepatic tissues, cortisol increases protein breadown, leading to

increased Lamino acidsJ availability in plasma.

iii. easons o increased catabolism:a. nhances synthesis o ey en?ymes o amino acid catabolism lie

transaminases, tyrosine transaminase, tryptophan pyrrolase, etc.

b. !lso there is decreased incorporation o amino acids in protein molecule.

d. Mver8all e0ect on protein metabolism by cortisol is G4egative 4itrogen @alance.

8. Efects on :ater and electrol$te meta1olism!

a. water metabolism is mediated through antidiuretic hormone (!3H).

b. 3efciency o glucocorticoids causes increased production o !3H. !3H decreases glomerular

fltration rate causing water retention in the body.

;. Efects on the immune s$stem !

a. ortisol suppress the host immune response. The steroid hormones act at di0erent levels8damaging lymphocytes, impairment o antibody synthesis, suppression o inNammatory

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viii. 3ecreases the number o circulating lymphocytes (lymphopenia), eosinophils and

monocytes.

B. Other ph$sioloical efects o" lucocorticoids:

a. lucocorticoids are involved in several physiological unctions.

b. %timulate the fght and Night response (to ace sudden emergencies) o catecholamine

c. 2ncrease the production o gastric H2 and pepsinogen.

d. lnhibit the bone ormation, hence the sub;ects are at a ris or osteoporosis.

Mechanism o" action o" lucocorticoids !

-. %teroid hormone di0uses across the plasma

membrane o its target cell and binds to a specifc

cytosolic receptor in the cells o

liver,muscles, adipose tissue, lymphoid tissue, sin,

bone, fbroblasts, etc.

/. %teroid receptor molecule has three distinct

domains:a. ! steroid binding domain

b. ! 34! binding domain

c. ! transcription8activating domain.

1. ! heat8shoc protein, hap OP, binds to the receptor in the absence o hormone and prevents

activation o the receptor protein. %teroid binding causes dissociation o the Ghsp OP.

5. The steroid8receptor complex enters the nucleus, and bind by 34!8binding site called the Hormone

responsive element (H) through a ?inc8fnger moti and activate the gene promoter seCuence o

34!, causing transcription.

Mineralocorticoid hormones !

-. The most active and potent mineralocorticoid is aldosterone. lt promotes 4a9 reabsorption at thedistal convoluted tubules o idney. 4a9 retention is accompanied by corresponding excretion o

*9, H9 and 4H ions.

/. egulation o aldosterone synthesis : The production o aldosterone is regu.lated by di0erent

mechanisms. These include reninangiotensin, potassium, sodium and !TH.

1. "echanism o aldosterone action : !ldosterone acts lie other steroid hormones. &t binds with

specifcr eceptorso n the targett issue and promotes transcription and translation.

Meta1olism o" adrenocorticosteroids:

-. The steroid hormones are metaboli?ed in the liver and excreted in urine as con;ugates o

glucuronides or sulates.

/. The urine contains mainly two steroids8 -A 8hydroxysteroid s an d -A8etosteroids8derived rom themetabolism o glucocorticoids and mineralocorticoids. !ndrogens synthesi?ed by gonads also

contribute to the ormation o - A8etosteroids.

1. +rinary -A8etosteroids estimated in the laboratory are expressed in terms o

dehydroepiandrosterone and their normal excretion is in the range o M./8/.M mg'day.

ddison=s disease !

-. lmpairment in adrenocortical unction results in !ddison>s disease. This disorder is characteri?ed by

decreased blood glucose level (hypoglycemia), loss o weight, loss o appetite, muscle weaness,

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impaired cardiac unction, low blood pressurel, decreased 4a9 and increased * 9 level in serum,

increased susceptibility to stress etc.

ushin=s s$ndrome :

-. Hyperunction o adrenal cortex may be due to long term pharmacological use o steroids or tumor

o adrenal cortex or tumor o pituitary.

/. ushing>s syndrome is characteri?ed by hyperglycemia (due to increased gluconeogenesis), atigue,

muscle wasting, edema, osteoporosis, negative nitrogen balance, hypertension, moon8ace etc.

'H+ROD HORMONES

/. E>plain th$roid "unction tests and its importance %on Ma$ 223

. -ssessment o" h$poth$roidism

4. 'h$roid "unction 'ests

5. 6hat is primar$ h$perth$roidism7 Name the conditions causin t. %on Ma$ 2/2

8. H$poth$roidism presents :ith h$percholesterolemia. 6h$7

Mechanism o" -ction o" 'h$roid Hormone

-. The hormone attaches to specifc nuclear receptors. Then the receptor8hormone complex binds to

the 34!. The T1 receptor complex binding seCuence in the 34! or the thyroid responsive element

(T) has been identifed.

/. The T1 binding results in increase in transcription rate.

Meta1olic Efects o" 'h$roid Hormones

-. The hormone exerts action on every cell o the body. alorigenic e0ect or thermogenesis is the

ma;or e0ect o thyroid hormone. Mne mg o T5 will produce an excess o -PPP cal. This

thermogenic e0ect is mediated by uncoupling o oxidative phosphorylation.

/. @asal metabolic rate (@") is increased. Thyroxine increases cellular metabolism.1. arliest e0ect o T5 is stimulation o 4! synthesis and conseCuent increase in protein synthesis.

Higher concentration o T1 causes protein catabolism and negative nitrogen balance. &oss o body

weight is a prominent eature o hyperthyroidism.

5. luconeogenesis and carbohydrate oxidation are increased. lucose tolerance test shows rapid

absorption.

8. *att$ acid meta1olism is increased. #holesterol deradation is increased and hence

cholesterol level in 1lood is decreased? :hich is another hallmar@ o" h$perth$roidism.

+%ER'H+RODSM

-. Hyperthyroidsm may be due to:a. increase in binding protein

b. increased aQnity o binding protein

c. e0ects o autoantibodies

d. T%H secreting tumors

e. T5 toxicosis (T5 increase T1 low).

/. %rimar$ h$perth$roidism: t is due to diseases o thyroid gland. 2t is seen in:

a. raves> disease.

b. Toxic multinodular goiter,

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c. Toxic adenoma,

d. $unctioning metastatic thyroid carcinoma,

e. Tsh receptor mutation,

. %truma ovarii (teratomas o ovary),

g. 2odine excess.

1. Secondar$ h$perth$roidism is due to diseases o pituitary or hypothalamus). 2t is seen in:

a. T%H secreting pituitary adenoma,

b. Thyroid hormone resistance syndrome,

c. horionic gonadotropin secreting tumors

d. estational thyrotoxicosis.

+%O'H+RODSM!

-. %rimar$ h$poth$roidism is due to diseases o thyroid gland. 2t is seen in:

a. !uto immune hypothyroidism (e.g. HashimotoJs thyroiditis),

b. Thyroidectomy and

c. adiation therapy.

d. 3rugs producing hypothyroidism are &ithium, antithyroid drugs and para aminosalicylicacid.

e. ongenital hypothyroidism is seen in:

i. 2odine defciency,

ii. !bsent or ectopic thyroid gland,

iii. 3yshormonogenesis

iv. T%H receptor mutation.

/. Secondar$ h$poth$roidism is due to diseases o #ituitary or Hypothalamus.

a. Hypopituitarism is caused by:

i. #ituitary tumors,

ii. #ituitary surgery or irradiation, infltration,iii. %heehanJs syndrome and

iv. 2solated T%H defciency.

b. Hypothalamic diseases causing secondary hypothyroidism are:

i. Tumors,

ii. Trauma and

iii. "alignant infltration.

h$roid *unction 'ests!

+%O'H+RODSM!

-. MR! "easuremento basal metabolic rate was once used to reNect thyroid activity. 2t is low in

hypothyroidism./. %: The estimation o serum protein bound iodine (#@l), representing the circulating thyroid

hormones, was employed or a long time to assess thyroid unction. The normal serum #@2

concentration is 18B µg' -MM ml. Hypothyroidism is associated with decreased #@2

1. adioactive iodine uptae (!2+) and scanning o thyroid gland are also used or diagnosis.

5. Hormone assa$!

i. T5 is the main hormone produced by the thyroid. T1 is produced by peripheral conversion o

T5.

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ii. T1 and T5 are largely protein bound in the plasma, mainly to thyroxine8binding globulin

(T@). Mnly the unbound or >ree> portion ($T1, $T5) is active.

iii. 2n pregnancy and oral pills, estrogen causes the production o more T@ resulting in higher

levels o total T5 but the physiologically important ree T5 levels remain normal. This is also

why total T5 levels tend to be higher in women and $ree T5 estimation becomes necessary.

iv. The concentration o ree T1 and T5, and T%H are measured (by 2! or &2%!) and their serum

normal concentrations are:

-. $ree triiodothyronine (T1) : BP8//P ng'dl

/. $ree thyroxine (T5): P.B8/.5 ng'dl

1. Total thyroxine (T9): 68-/ ng'dl

5. Thyroid stimulating hormone (T%H): R-P µ+'ml

v. 2n Hypothyroidism:

i. T1 and T5 are reduced

ii. T%H:

-. 2n primary hypothyroidism, T%H level is elevated due to lac o eedbac.

/. @ut in secondary hypothyroidism, T%H, T1 and T5 levels are low this could pointto a pituitary or hypothalamic cause.

8. 'RH response test

iii. TH stimulates anterior pituitary to release thyroidstimulating hormone (T%H or

thyrotropin) which, in turn, stimulates the release o thyroid hormones (T1 and T5).

iv. TH administration will stimulate the production o T%H rom pituitary. 2 the

hypothalamopituitary8thyroid axis is normal, the T1 and T5 secretions will be increased.

v. Hypopituitarism. The pituitary could not respond to TH. 2n these cases the plasma

thyroid hormone levels are subnormal.

vi. !n exaggerated response is observed in primary hypothyroidism since the negative

eedbac e0ect o T5 is reduced.;. #holesterol!

vii. 2n hypothyroidism, cholesterol level in blood is increased. 2t is not diagnostic, because

hypercholesterolemia is seen not only in hypothyroidism, but also in diabetes mellitus,

hypertension, obstructive ;aundice and nephrotic syndrome.

viii. However, cholesterol level is a useul index in monitoring the e0ectiveness o the therapy

in thyroid conditions. #holesterol level is increased in h$poth$roidism? 1ecause

cholesterol carr$in lipoprotein deradation is decreased.

A. Radioactive iodine upta@e (R-U)

ix. adioactive 2odine uptae by thyroid gland and thyroid scanning with TcOO (radioactive

technicium) are o diagnostic value. These tests are contraindicated in pregnancy andchildhood.

x. 2odine uptae is reduces in primary hypothyroidism

B. Detection o" th$roid anti1odies

xi. 2n Hashimoto>s thyroiditis antimicrosomal antibodies, antithyroglobulin antibodies, and

antinuclear antibodies are detected in the circulation. They produce cell destruction and

eventual hypothyroidism.

+%ER'H+RODSM!

. -ssa$ o" hormones

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a. "easurement o T5 and T1 levels in blood by 2! (radio immuno assay) or by &2%! orm the

basis o laboratory diagnosis o thyroid diseases.

b. 2n hyperthyroidism:

-. @oth T1 and T5 levels are increased

/. T%H is reduced due to eedbac inhibition.

1. $ree T1 and T5: These are more sensitive tests since the values o ree hormones

are not a0ected by the amount o carrier proteins (T@) in the blood. Hence

useul during pregnancy.

. %lasma 'SH

a. Hyperthyroidism due to primary thyroid disease has high T1 and T5 levels, but suppressed T%H

levels.

b. Hyperthyroidism due to pituitary cause is indicated by high T%H, T1 and T5 levels.

. 'RH response test

-. TH administration will stimulate the production o T%H. 2 the hypothalamopituitary8thyroid axis

is normal, the T1 and T5 secretions will be increased.

/. 2n hyperthyroidism. The negative eedbac e0ect o high T5 overpowers the stimulant e0ect o TH. Here the thyroid hormone levels are elevated.

. #holesterol!

-. 2t is decreased in hyperthyroidism.

/. holesterol estimation will be o no value in the assessment o thyroid unction since cholesterol

level is elevated in many other disorders

. Radioactive iodine upta@e (R-U)

-. adioactive 2odine uptae by thyroid gland and thyroid scanning with TcOO (radioactive

technicium) are o diagnostic value. These tests are contraindicated in pregnancy and childhood.

/. 2t will indicate thyroid hyperunction.

. Detection o" th$roid anti1odies-. 2n rave>s disease (Hyperthyroidism) , the presence o thyroid stimulating immunoglobulin

(T%2g), also nown as long acting thyroid stimulator (&!T%) is seen in circulation. The &!T% can

bind to T%H receptors on thyroid gland and produce stimulation which is not under eedbac

control. The T%2g is an antibody generated against the T%H receptor.

*UN#'ONS O* %-R-'H+ROD HORMONE

. Meta1olic conseCuences o" administration o" %'H are!

i. 2ncrease in serum a99 concentration.

ii. 3ecrease in serum inorganic #M5 concentration.iii. 2ncreased urinary a99 ollowing an initial decrease.

iv. 2ncreased urinary #M5 .

v. emoves a rom bones, particularly i dietary intae o a is inadeCuate.

vi. 2ncrease in LcitrateJ content o blood plasma, idney and bones.

it.D! 2increase the rate o conversion o /68MH8cholecalcierol to -,/68di8MH8cholecalcierol, by

stimulating =8-8 hydroxylase en?yme.

M meta1olism: 2ncrase urinary excretion o "g

idne$s:

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i. #TH acts through by increasing c8!"#.

ii. #TH binds to specifc LreceptorsJ on plasma membrane o renal cortical cells o both proximal

and distal tubules and stimulates adenyl cyclase to produce c8!"#.

iii. c8!"# then is transported to apical'luminal part o the cell where it activates c8!"# dependent

protein inase, which phosphorylates specifc proteins o the apical membrane to a0ect the

several mineral transport, across the membrane.

iv. #TH decreases the transmembrane transport and reabsorption o fltered #i in both proximal and

distal tubular cells and increases the urinary excretion o inorganic phosphate (phosphaturic

e0ect)

v. $all in serum inorganic #M5 level leads to mobilisation o #M5 rom bones, which also mobilises

a99 along with, resulting to hypercalcaemia.

vi. #TH stimulates =8-8hydroxylase en?yme located in mitochondria o proximal convoluted tubule

cells, which converts /68MHcholecalcierol, to -8/6, di8MH8cholecalcierol which in turn increases

the intestinal and renal absorption o a99 resulting to hypercalcaemia.

vii. #TH inhibits the transmembrane transport o *9 and HM1< to decrease their reabsorption by

renal tubules.viii. #TH increases the transmembrane transport and reabsorption o fltered a99 in the distal

tubules resulting initially to decrease urinary excretion o a99. @ut later on, #TH8induced

hypercalcaemia enhances the amount o fltered a99 which increases the renal excretion.

-ction on ones:

i. #TH binds to specifc LreceptorsJ present on membranes o osteoclasts, osteoblasts and

osteocytes and increases cyclic !"# level in these cells, which acts through c8!"# dependent

protein inases. $ollowing actions are seen:

ii. Msteoclastic activity: 2t stimulates the di0erentiation and maturation o precursors cells o

osteoclasts to mature osteoclasts.

iii. Msteoclastic osteolysis: #TH stimulates the osteoclasts through Gsecond messenger c8!"# toincrease the resorption o bones which enhances mobilisation o a and # rom bones.

iv. Msteocytic osteolysis: #TH also stimulates osteocytes which increases bone resorption thus

mobilising a99 and #i. There occurs enlargement o bone lacunae.

v. !ction on alaline phosphatase: !laline phosphatase activity varies as per #TH concentration.

!t low concentrations, #TH stimulates the sulation o cartilages and increases the number o

osteoblasts and alaline phosphatase activity o bone osteoblasts. !t higher levels o

physiological concentrations, #TH inhibits alaline phosphatase activity and collagen synthesis

in osteoblasts and decreases the a99 retaining capacity o bones. #TH induced rise in

intracellular c8!"# in osteoclasts'and osteocytes leads to secretion o lysosomal hydrolases'and

collagenases which increase breadown o collagen and "#% in bones matrices.. -ction on ntestinal Mucosa!

i. #TH does not act directly on intestinal mucosal cells as the cells do not possess the specifc

LreceptorsJ or #TH. @ut it increases the absorption o a99 and #M5 through production, -8/6,

di8MH8cholecalcierol (calcitriol).

*UN#'ONS O* G,U#-GON.(S.N)

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-. 2t is a polypeptide hormone with /O amino acids. 2t is secreted by the alpha cells o pancreas.

lucagon is synthesi?ed as a longer proglucagon precursor. lucagon has a hal8lie in plasma at

about 6 minutes. 2t is inactivated in the liver. The ma;or regulator o secretion o glucagon is

glucose. !n increase in blood glucose level inhibits secretion o glucagon.

h$sioloical -ctions o" Glucaon

/. lucagon is the most potent hyperglycemic hormone. 2t is anti8insulin in nature.

1. lucagon is mainly glycogenolytic. The active orm o glycogen phosphorylase is ormed under the

inNuence o glucagon. &iver is the primary target or the glycogenolytic e0ect o glucagon.

5. 2t depresses glycogen synthesis.

6. luconeogenesis is avored by glucagon by inducing en?ymes lie ##*, glucose878 phosphatase

and ructose8-,78bisphosphatase.

7. lucagon increases plasma ree atty acid level. 2n adipose tissue glucagon avors beta8oxidation,

as it activates carnitine acyl transerase. The mitochondrial acetyl o! level increases

A. *etogenesis is avored.

Mechanism o" action

-. lucagon combines with a membrane bound receptor. This activates the 3#8bound 8protein, byconverting it into T# orm.

/. The alpha subunit o the protein dissociates rom the beta and gamma subunits. The alpha

subunit binds to T#. The T#8 protein will in turn activate adenylate cyclase to convert !T# to

c!"#.

1. yclic !"# is the second messenger, which combines with the regulatory subunit o the protein

inase so that the catalytic subunit is ree to act.

5. The active protein inase will phosphorylate en?yme proteins and alter their activity covalent

modifcation and activation o glycogen phosphorylase, inactivation o glycogen synthase, etc.

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Documents

17. Hormones& Signal Transduction