Hormonal signal transduction

 Hormones

are released as part of the general adaptive response to external or internal stimuli  As first step they interact with specific receptors on/in target tissues.

 Hormone

receptor interaction results in generation of intracellular signal that can either regulate the activity of a select set of genes, or affect the activity of specific proteins including enzymes and transporter or channel proteins.

 The

final outcome of the signal may result in protein synthesis, cell growth and replication….  Many other signaling molecules using the same mechanisms include; cytokines, growth factors, metabolites…

 According to the location of specific cellular receptor hormones are classified into two groups:  Group I interact with an intra cellular receptor  Group II with membrane bound receptors .

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.  The hormone receptor complex first undergoes activation reaction. Group I hormones (lipophilic hormones):  They diffuse through the plasma membrane to encounter intracellular receptors which can be in the cytosol or the nucleus.

. Binding of Glucocorticoids to their receptor in the cytosol results in release of heat shock protein from the receptor and then the complex is transferred to the nucleus  The receptor also contains nuclear localization sequences that assist in the translocation from the cytosol to the nucleus.  In the nucleus the complex binds with high affinity to DNA sequence (HRE).

The DNA-bound. liganded receptor serves as a high affinity binding site for one or more coactivator proteins This results in accelerated gene transcription .

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 The thyroid hormones and retinoids diffuse across the plasma membrane and reach the nucleus  The cognate receptor for these is already bound to HRE (TRE or RARE).  The DNA bound receptor in the absence of the specific ligand is bound to corepressor protein and inhibit transcription. .

 The binding of the ligand releases the corepressor and the receptor-hormone complex now binds a coactivator (s) resulting in activation of gene transcription. . the tissue this process results in specific proteins needed for metabolic activities or….  Depending on the hormone.

 They initiate cellular responses after binding to the extracellular domain of membrane bound receptors. .Group II hormones (peptides and catecholamines)  They have no carriers in the blood and they have short half in blood circulation.

 Their action is more rapid as compared with group I hormones  Intracellular second messenger or signaling pathways can be one of the following: . but can also affect transcription. These hormones mainly modulate activity of existing proteins.

protein kinase C pathway  3.protein kinase G pathway  4.tyrosine Kinases  5. .Calcium/calmodulin dependent protein kinase CaM pathway  6.protein kinase A pathway  2. The signaling pathways:  1.ligand-gated and voltage-gated ion channels.

and C are called G protein-coupled Receptors (GPCR). GTP-binding protein (G protein) links the hormone receptor complex with the effector enzyme eg AC. or PLC. .Receptors using protein kinase A.

FSH. PTH. NSH. CRH .TSH. αs αi  Glucagon.cAMP dependent PKA pathway  Many hormones can stimulate synthesis of cAMP from ATP by adenylyl cyclase and others inhibit the synthesis. epinephrene. ACTH. LH.  Stimulatory s(s) or inhibitory (i)  Gs and Gi. hCG.

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 Cholera toxin and Pertussis toxin catalyse ADP-ribosylation of αs and αi respectively. thus a subunit can not reassociate with the beta gamma subunits and result in sustain activity of the G protein….  In case of as the binding of cholera toxin disrupts the GTP-ase activity.  Many families of the G proteins with wide range effects .

 cAMP formed by AC binds PKA which a heterodimer molecule consisting of two regulatory subunits R and catalytic subunits C. .  cAMP binds the R subunit and results in dissociation of the C which becomes activated.

steroidogenesis. secretion. The active C subunit phosphorylates a variety of cellular enzymes on serine and threonine residues at specific sites (R/K-X-S/T and R-K-XX-S). .  Different effects of cAMP such as glycogenolysis. synaptic transmission…are mediated by phosphorylation of the specific enzymes. ion transport. lipolysis. enzyme induction.

 It is also active when it is phosphorylated by PKA by binding a coactivator protein. . cAMP effects on transcription are mediated by the protein cyclic AMP response element binding protein (CREB).

 The action of cAMP-dependent enzymes is terminated by hydrolysis of cAMP to 5’-AMP by phosphodiesterases (PDE).  Inhibitors of PDE such caffeine increase intracellular cAMP and mimic or prolong the actions of hormones through this signal .

 It is hydrolysed to DAG and IP3 by the enzyme phospholipase C .Protein kinase C pathway  The membrane glycerophospholipid phosphatidylinositol 4.5 bisphosphate is also involved in hormonal signal transduction.

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The receptors for acetylcholine. angiogenin. TRH…when coupled by their respective ligands they activate PLC. which is attached to the inner leaflet of the plasma membrane. GRP. ADH. They first activate Gq protein which is similar to Gs. .

 DAG activates protein kinase C (PKC) in the presence of Ca2+.5 triphosphate (IP3).  IP3 by interacting with a specific intracellular receptor. Hydrolysis results in two second messengers. is an effective releaser of Ca2+ from intracellular storage (ER).4. . Diacylglycerol (DAG) and inositol 1.

 The action of a group of compounds known as tumor promoters.  There several isoenzymes of PKC in different tissues. . PKC phosphorylates many cellular proteins on serine and threonine residues. is attributable to their effects on PKC. such phorbol esters.

but unlike DAG they are not rapidly metabolized and give sustained action.  Lethium as antidepressant… . They mimic cellular DAG as second messengers.

 It is normally kept very low in the cytosol < 10-7 M by the action of Ca2+ pump in the ER. cytoskeleton rearrangements. muscle contraction. mitochondria and plasma membrane .Calcium as second messenger  Calcium triggers many cellular responses such as exocytosis in neurons and endocrine cells.

neuronal or other signals cause either influx of Ca2+ into the cell through specific Ca2+ channels in the plasma membrane or release of sequestered Ca2+ in ER or mitochondria raising cytosolic calcium. Hormonal. .

 Changes in intracellular Ca2+ are detected by calcium-binding proteins that regulate a variety of calcium dependent enzymes. the binding of Ca to calmodulin drives conformational change. .  When intracellular calcium rises to about 10-6 M. M 17000) is an acidic protein with four high affinity Calcium binding sites.  Calmodulin (CaM.

 Calmodulin is a member of calcium binding proteins that also includes troponin. modulates their activities. which triggers skeletal muscle contraction in response to increased calcium . Calmodulin associates with a variety of proteins and. in its calcium-bound state.

calmodulin binds calcium. and activates CaM kinase.  When intracellular calcium is increased in response to some stimulus.  The kinase then phosphorylates a number of target enzymes. . Calmodulin is an integral subunit of Ca2+/calmodulin-dependent protein kinase (CaM kinase). undergoes a change in conformation. regulating their activity (synapsin 1).

 Thus. Calmodulin is also regulatory subunit of phosphorylase b kinase in the muscle which is activated by calcium. calcium triggers ATPrequiring muscle contraction while also activating glycogen breakdown. providing fuel for ATP synthesis. .

Ligand-gated ion channels .

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diuresis.cGMP dependent protein kinase G  cGMP is synthesized GTP by guanylyl cyclase (GC) which exists in soluble and membrane bound form. vasodilation and inhibition of aldosterone secretion.  It acts by binding membrane bound GC which synthesizes cGMP from GTPPKG .  Atrio-natriuretic Factor (ANF) causes natriuresis.

all cause smooth muscle relaxation and are potent vasodilators. NO.  They activate soluble GC.  Inhibitors of cGMP PDE enhance and prolong these responses (sildenafil. sodium azide. Viagra). . nitroglycerin. Many compounds including nitroprusside.

IGF receptors contain intrinsic ligand-activated tyrosine kinase activity. differentiation and the inflammatory response have this intrinsic tyrosine kinase activity. Insulin.  Many receptors involved growth control.Tyrosine kinases  EGF. .

phosphatases…. Ligand receptor interaction results in a tyrosine phosphorylation event that initiates a cascade which may involve several protein kinases. .

.  When the hormone is bound it is autophosphorylated on specific tyrosine residues.Insulin receptor  The insulin receptor is a heterodimer composed of two identical alpha subunits and two beta subunits.

at least 4 IRSs exist. the phosphorylated receptor phosphorylates IRSs on tyrosine residues. Then.  IRS binds the Src homology 2 (SH2) domains of a variety of proteins that are directly involved in mediating different effects of insulin:  PI-3 kinase PDK1…. .

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Decreases lipolysis Decreases gluconeogenesis Increases lipogenesis Increase protein synthesis and decreases protein degradation .

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Kh. 2005 ATP cAMP Protein kinase-A Slide 69 R2C2(inactive) FA Protein kinase-A Hormone 2C(active) + R2-cAMP TAG-lipase (active) TAG-lipase (inactive) FA FA Phospho-protein Phosphatase (inactive) TAG . Atif.Hormone-Receptor Adenylate-cyclase (Inactive) Adenylate-cyclase (active) Copy Right H.