hormonal signal transduction
TRANSCRIPT
Hormonal signal Hormonal signal transductiontransduction
Hormones are released as Hormones are released as part of the general adaptive part of the general adaptive response to external or response to external or internal stimuliinternal stimuli
As first step they interact As first step they interact with specific receptors on/in with specific receptors on/in target tissues.target tissues.
Hormone receptor interaction Hormone receptor interaction results in generation of results in generation of intracellular signal that can intracellular signal that can either regulate the activity of either regulate the activity of a select set of genes, or a select set of genes, or affect the activity of specific affect the activity of specific proteins including enzymes proteins including enzymes and transporter or channel and transporter or channel proteins.proteins.
The final outcome of the The final outcome of the signal may result in protein signal may result in protein synthesis, cell growth and synthesis, cell growth and replication….replication….
Many other signaling Many other signaling molecules using the same molecules using the same mechanisms include; mechanisms include; cytokines, growth factors, cytokines, growth factors, metabolites…metabolites…
According to the location of According to the location of specific cellular receptor specific cellular receptor hormones are classified into hormones are classified into two groups:two groups:
Group I interact with an intra Group I interact with an intra cellular receptorcellular receptor
Group II with membrane Group II with membrane bound receptorsbound receptors
Group I hormones (lipophilic Group I hormones (lipophilic hormones):hormones):
They diffuse through the They diffuse through the plasma membrane to plasma membrane to encounter intracellular encounter intracellular receptors which can be in the receptors which can be in the cytosol or the nucleus.cytosol or the nucleus.
The hormone receptor The hormone receptor complex first undergoes complex first undergoes activation reaction.activation reaction.
Binding of Glucocorticoids to Binding of Glucocorticoids to their receptor in the cytosol their receptor in the cytosol results in release of heat shock results in release of heat shock protein from the receptor and protein from the receptor and then the complex is transferred then the complex is transferred to the nucleusto the nucleus
The receptor also contains The receptor also contains nuclear localization sequences nuclear localization sequences that assist in the translocation that assist in the translocation from the cytosol to the nucleus.from the cytosol to the nucleus.
In the nucleus the complex binds In the nucleus the complex binds with high affinity to DNA with high affinity to DNA sequence (HRE).sequence (HRE).
The DNA-bound, liganded The DNA-bound, liganded receptor serves as a high receptor serves as a high affinity binding site for one affinity binding site for one or more coactivator or more coactivator proteinsproteins
This results in accelerated This results in accelerated gene transcriptiongene transcription
The thyroid hormones and The thyroid hormones and retinoids diffuse across the retinoids diffuse across the plasma membrane and reach the plasma membrane and reach the nucleus nucleus
The cognate receptor for these The cognate receptor for these is already bound to HRE (TRE or is already bound to HRE (TRE or RARE).RARE).
The DNA bound receptor in the The DNA bound receptor in the absence of the specific ligand is absence of the specific ligand is bound to corepressor protein bound to corepressor protein and inhibit transcription.and inhibit transcription.
The binding of the ligand The binding of the ligand releases the corepressor and releases the corepressor and the receptor-hormone complex the receptor-hormone complex now binds a coactivator (s) now binds a coactivator (s) resulting in activation of gene resulting in activation of gene transcription.transcription.
Depending on the hormone, Depending on the hormone, the tissue this process results the tissue this process results in specific proteins needed for in specific proteins needed for metabolic activities or….metabolic activities or….
Group II hormones (peptides Group II hormones (peptides and catecholamines)and catecholamines)
They have no carriers in the They have no carriers in the blood and they have short blood and they have short half in blood circulation.half in blood circulation.
They initiate cellular They initiate cellular responses after binding to responses after binding to the extracellular domain of the extracellular domain of membrane bound receptors.membrane bound receptors.
These hormones mainly These hormones mainly modulate activity of existing modulate activity of existing proteins, but can also affect proteins, but can also affect transcription.transcription.
Their action is more rapid as Their action is more rapid as compared with group I compared with group I hormoneshormones
Intracellular second Intracellular second messenger or signaling messenger or signaling pathways can be one of the pathways can be one of the following:following:
The signaling pathways:The signaling pathways:1- protein kinase A pathway1- protein kinase A pathway2- protein kinase C pathway2- protein kinase C pathway3- protein kinase G pathway3- protein kinase G pathway4- tyrosine Kinases4- tyrosine Kinases5- Calcium/calmodulin 5- Calcium/calmodulin
dependent protein kinase CaM dependent protein kinase CaM pathwaypathway
6- ligand-gated and voltage-6- ligand-gated and voltage-gated ion channels.gated ion channels.
Receptors using protein Receptors using protein kinase A, and C are called kinase A, and C are called G protein-coupled G protein-coupled Receptors (GPCR).Receptors (GPCR).
GTP-binding protein (G GTP-binding protein (G protein) links the hormone protein) links the hormone receptor complex with the receptor complex with the effector enzyme eg AC, or effector enzyme eg AC, or PLC. PLC.
cAMP dependent PKA cAMP dependent PKA pathwaypathway
Many hormones can stimulate Many hormones can stimulate synthesis of cAMP from ATP by synthesis of cAMP from ATP by adenylyl cyclase and others adenylyl cyclase and others inhibit the synthesis.inhibit the synthesis.
Stimulatory Stimulatory ss(s) or inhibitory (i)(s) or inhibitory (i)Gs and Gi. Gs and Gi. ααss ααii Glucagon, epinephrene, ACTH, Glucagon, epinephrene, ACTH,
FSH, hCG, NSH,TSH, PTH, LH, CRHFSH, hCG, NSH,TSH, PTH, LH, CRH
Cholera toxin and Pertussis toxin Cholera toxin and Pertussis toxin catalyse ADP-ribosylation of catalyse ADP-ribosylation of ααss and and ααii respectively. respectively.
In case of as the binding of In case of as the binding of cholera toxin disrupts the GTP-cholera toxin disrupts the GTP-ase activity, thus a subunit can ase activity, thus a subunit can not reassociate with the beta not reassociate with the beta gamma subunits and result in gamma subunits and result in sustain activity of the G protein….sustain activity of the G protein….
Many families of the G proteins Many families of the G proteins with wide range effects with wide range effects
cAMP formed by AC binds cAMP formed by AC binds PKA which a heterodimer PKA which a heterodimer molecule consisting of two molecule consisting of two regulatory subunits R and regulatory subunits R and catalytic subunits C .catalytic subunits C .
cAMP binds the R subunit cAMP binds the R subunit and results in dissociation of and results in dissociation of the C which becomes the C which becomes activated.activated.
The active C subunit The active C subunit phosphorylates a variety of phosphorylates a variety of cellular enzymes on serine and cellular enzymes on serine and threonine residues at specific threonine residues at specific sites (R/K-X-S/T and R-K-X-X-S).sites (R/K-X-S/T and R-K-X-X-S).
Different effects of cAMP such Different effects of cAMP such as glycogenolysis, lipolysis, as glycogenolysis, lipolysis, steroidogenesis, secretion, ion steroidogenesis, secretion, ion transport, enzyme induction, transport, enzyme induction, synaptic transmission…are synaptic transmission…are mediated by phosphorylation of mediated by phosphorylation of the specific enzymes.the specific enzymes.
cAMP effects on transcription cAMP effects on transcription are mediated by the protein are mediated by the protein cyclic AMP response element cyclic AMP response element binding protein (CREB).binding protein (CREB).
It is also active when it is It is also active when it is phosphorylated by PKA by phosphorylated by PKA by binding a coactivator protein.binding a coactivator protein.
The action of cAMP-The action of cAMP-dependent enzymes is dependent enzymes is terminated by hydrolysis of terminated by hydrolysis of cAMP to 5’-AMP by cAMP to 5’-AMP by phosphodiesterases (PDE).phosphodiesterases (PDE).
Inhibitors of PDE such Inhibitors of PDE such caffeine increase intracellular caffeine increase intracellular cAMP and mimic or prolong cAMP and mimic or prolong the actions of hormones the actions of hormones through this signalthrough this signal
Protein kinase C pathwayProtein kinase C pathwayThe membrane The membrane
glycerophospholipid glycerophospholipid phosphatidylinositol 4,5 phosphatidylinositol 4,5 bisphosphate is also involved bisphosphate is also involved in hormonal signal in hormonal signal transduction.transduction.
It is hydrolysed to DAG and IPIt is hydrolysed to DAG and IP33 by the enzyme phospholipase Cby the enzyme phospholipase C
The receptors for The receptors for acetylcholine, ADH, acetylcholine, ADH, angiogenin, GRP, TRH…angiogenin, GRP, TRH…when coupled by their when coupled by their respective ligands they respective ligands they activate PLC, which is activate PLC, which is attached to the inner leaflet attached to the inner leaflet of the plasma membrane.of the plasma membrane.
They first activate GThey first activate Gqq protein which is similar to protein which is similar to Gs.Gs.
Hydrolysis results in two Hydrolysis results in two second messengers; second messengers; Diacylglycerol (DAG) and Diacylglycerol (DAG) and inositol 1,4,5 triphosphate inositol 1,4,5 triphosphate (IP(IP33).).
DAG activates protein kinase C DAG activates protein kinase C (PKC) in the presence of Ca(PKC) in the presence of Ca2+2+..
IPIP33 by interacting with a by interacting with a specific intracellular receptor, specific intracellular receptor, is an effective releaser of Cais an effective releaser of Ca2+2+ from intracellular storage (ER).from intracellular storage (ER).
PKC phosphorylates many PKC phosphorylates many cellular proteins on serine cellular proteins on serine and threonine residues.and threonine residues.
There several isoenzymes of There several isoenzymes of PKC in different tissues.PKC in different tissues.
The action of a group of The action of a group of compounds known as tumor compounds known as tumor promoters, such phorbol promoters, such phorbol esters, is attributable to their esters, is attributable to their effects on PKC.effects on PKC.
They mimic cellular DAG as They mimic cellular DAG as second messengers, but second messengers, but unlike DAG they are not unlike DAG they are not rapidly metabolized and give rapidly metabolized and give sustained action.sustained action.
Lethium as antidepressant… Lethium as antidepressant…
Calcium as second Calcium as second messengermessenger
Calcium triggers many cellular Calcium triggers many cellular responses such as exocytosis in responses such as exocytosis in neurons and endocrine cells, neurons and endocrine cells, muscle contraction, cytoskeleton muscle contraction, cytoskeleton rearrangements.rearrangements.
It is normally kept very low in the It is normally kept very low in the cytosol < 10cytosol < 10-7-7 M by the action of M by the action of CaCa2+2+ pump in the ER, mitochondria pump in the ER, mitochondria and plasma membraneand plasma membrane
Hormonal, neuronal or other Hormonal, neuronal or other signals cause either influx of signals cause either influx of CaCa2+2+ into the cell through into the cell through specific Caspecific Ca2+2+ channels in the channels in the plasma membrane or release plasma membrane or release of sequestered Caof sequestered Ca2+2+ in ER or in ER or mitochondria raising mitochondria raising cytosolic calcium. cytosolic calcium.
Changes in intracellular CaChanges in intracellular Ca2+2+ are are detected by calcium-binding detected by calcium-binding proteins that regulate a variety proteins that regulate a variety of calcium dependent enzymes. of calcium dependent enzymes.
Calmodulin (CaM; M 17000) is an Calmodulin (CaM; M 17000) is an acidic protein with four high acidic protein with four high affinity Calcium binding sites.affinity Calcium binding sites.
When intracellular calcium rises When intracellular calcium rises to about 10to about 10-6-6 M, the binding of M, the binding of Ca to calmodulin drives Ca to calmodulin drives conformational change.conformational change.
Calmodulin associates with a Calmodulin associates with a variety of proteins and, in its variety of proteins and, in its calcium-bound state, calcium-bound state, modulates their activities.modulates their activities.
Calmodulin is a member of Calmodulin is a member of calcium binding proteins that calcium binding proteins that also includes troponin, which also includes troponin, which triggers skeletal muscle triggers skeletal muscle contraction in response to contraction in response to increased calciumincreased calcium
Calmodulin is an integral subunit of Calmodulin is an integral subunit of CaCa2+2+/calmodulin-dependent protein /calmodulin-dependent protein kinase (CaM kinase).kinase (CaM kinase).
When intracellular calcium is When intracellular calcium is increased in response to some increased in response to some stimulus, calmodulin binds calcium, stimulus, calmodulin binds calcium, undergoes a change in undergoes a change in conformation, and activates CaM conformation, and activates CaM kinase.kinase.
The kinase then phosphorylates a The kinase then phosphorylates a number of target enzymes, number of target enzymes, regulating their activity (synapsin regulating their activity (synapsin 1). 1).
Calmodulin is also regulatory Calmodulin is also regulatory subunit of phosphorylase b subunit of phosphorylase b kinase in the muscle which is kinase in the muscle which is activated by calcium.activated by calcium.
Thus, calcium triggers ATP-Thus, calcium triggers ATP-requiring muscle contraction requiring muscle contraction while also activating while also activating glycogen breakdown, glycogen breakdown, providing fuel for ATP providing fuel for ATP synthesis.synthesis.
Ligand-gated ion channelsLigand-gated ion channels
cGMP dependent protein cGMP dependent protein kinase Gkinase G
cGMP is synthesized GTP by guanylyl cGMP is synthesized GTP by guanylyl cyclase (GC) which exists in soluble cyclase (GC) which exists in soluble and membrane bound form.and membrane bound form.
Atrio-natriuretic Factor (ANF) causes Atrio-natriuretic Factor (ANF) causes natriuresis, diuresis, vasodilation natriuresis, diuresis, vasodilation and inhibition of aldosterone and inhibition of aldosterone secretion.secretion.
It acts by binding membrane bound It acts by binding membrane bound GC which synthesizes cGMP from GC which synthesizes cGMP from GTPGTPPKGPKG
Many compounds including Many compounds including nitroprusside, nitroglycerin, nitroprusside, nitroglycerin, NO, sodium azide, all cause NO, sodium azide, all cause smooth muscle relaxation smooth muscle relaxation and are potent vasodilators.and are potent vasodilators.
They activate soluble GC.They activate soluble GC.Inhibitors of cGMP PDE Inhibitors of cGMP PDE
enhance and prolong these enhance and prolong these responses (sildenafil, Viagra).responses (sildenafil, Viagra).
Tyrosine kinasesTyrosine kinasesEGF, Insulin, IGF receptors EGF, Insulin, IGF receptors
contain intrinsic ligand-activated contain intrinsic ligand-activated tyrosine kinase activity.tyrosine kinase activity.
Many receptors involved growth Many receptors involved growth control, differentiation and the control, differentiation and the inflammatory response have this inflammatory response have this intrinsic tyrosine kinase activity.intrinsic tyrosine kinase activity.
Ligand receptor interaction Ligand receptor interaction results in a tyrosine results in a tyrosine phosphorylation event that phosphorylation event that initiates a cascade which may initiates a cascade which may involve several protein involve several protein kinases, phosphatases…. kinases, phosphatases….
Insulin receptorInsulin receptorThe insulin receptor is a The insulin receptor is a
heterodimer composed of two heterodimer composed of two identical alpha subunits and identical alpha subunits and two beta subunits.two beta subunits.
When the hormone is bound When the hormone is bound it is autophosphorylated on it is autophosphorylated on specific tyrosine residues.specific tyrosine residues.
Then, the phosphorylated Then, the phosphorylated receptor phosphorylates IRSs receptor phosphorylates IRSs on tyrosine residues, at least on tyrosine residues, at least 4 IRSs exist.4 IRSs exist.
IRS binds the Src homology 2 IRS binds the Src homology 2 (SH2) domains of a variety of (SH2) domains of a variety of proteins that are directly proteins that are directly involved in mediating involved in mediating different effects of insulin:different effects of insulin:
PI-3 kinasePI-3 kinase PDK1…. PDK1….
Decreases lipolysisDecreases lipolysisDecreases gluconeogenesisDecreases gluconeogenesisIncreases lipogenesis Increases lipogenesis Increase protein synthesis and Increase protein synthesis and decreases protein degradationdecreases protein degradation
Hormone
TAG-lipase(inactive)
ATP
Adenylate-cyclase(Inactive)
Hormone-Receptor
Adenylate-cyclase(active)
cAMP
Protein kinase-AR2C2(inactive)
Protein kinase-A2C(active) + R2-cAMP
TAG-lipase(active)
DAGMAGTAG
Phospho-protein Phosphatase (inactive)
Glycerol
FAFA
FAFA
FAFA
Copy RightH. Kh. Atif.
2005
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