Signal transduction

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Transcript Signal transduction

Basic concepts of Metabolism
Metabolism and metabolic pathway
• Metabolic Map
• Catabolism
• Anabolism
- Regulation of Metabolism
• Signals from within the cell (Intracellular)
• Communication between cells.
- Biosignaling: Signal transduction
* Transduction by Intracellular receptors
* Transduction by Cell-surface receptors
a. Ligand-Gated Ion channels
b. Receptor enzyme
c. Receptors involving second messenger molecules
i. Adenylate cyclase system
ii. Phosphatidylinositol system
iii. Ca+ as second messenger
* Other messenger systems
a. cGMPs
b. Nitric oxide
References:
chapter 8 of Lippincots
chapter 13 of Lehningers
* Enzymes catalyze different
reactions that don't occur in
isolation but organized into multi
step sequence called pathway.
* The product of one reaction will
be the substrate of the subsequent
reaction
* Different pathways intersect
forming an integrated reactions
collectively called Metabolism
* Metabolic Map
A picture containing the
central pathways of energy
metabolism. Each pathway is
composed of multienzyme
sequence and each enzyme
has catalytic or regulatory
features
The Metabolic Map
Shows the links between
pathways, indicates the
intermediates between
different cycles (pathways)
and shows the effect on
different intermediates if
one pathway is blocked
* Metabolic Map
It is a picture containing
the central pathways of
energy metabolism. Each
pathway is composed of
multienzyme sequence and
each enzyme has catalytic
or regulatory features
The Metabolic Map
Shows the links between
pathways, indicates the
intermediates between
different cycles (pathways)
and shows the effect on
different intermediates if
one pathway is blocked
Catabolic and Anabolic Pathways
Pathways can be classified as either catabolic (degradative) or anabolic
(synthetic)
Catabolic: degradation of complex molecules (polysaccharides, proteins)
into simple molecules like CO2, NH3 and water.
Catabolism is convergent process: a wide variety of molecules are
transformed into a few common end products
Anabolic reactions are the synthesis of complex molecules from simple
precursor.
Anabolic is divergent process in which few biosynthetic precursors form
a wide variety of polymeric or complex products.
Catabolism
- catabolic reactions provide chemical energy in the form of the ATP
from the degradation of the energy-rich fuel compound. The catabolism
is essential for providing energy necessary for building up the complex
compound
Energy generation occur in three steps
Stage I
Stage II
Stage III
Energy is librated from the transfer of electrons from NADH and FADH2
to O2 through the electron transport chain
Anabolism
- Anabolic reactions combine small
molecules as amino acids to form
large complexes as proteins. These
processes require energy which is
provided by the break down of ATP to
ADP
- The biosynthetic pathway usually is
different from degredative pathway
of the same compound so the two
processes respond to different
regulatory
- Anabolic reactions involve chemical
reduction in which the reducing power
is NADPH
Regulation of Metabolism
•Pathways of the metabolism must be coordinated so that the
catabolism and the anabolism must meet the needs of the cell.
• The cell is not present in isolation it present in a tissue, in which all
the cells communicate together with regulatory signals.
• Regulatory signals including hormones, nervous system and availability
of nutrients which affect the signals generated within the cell itself.
*Signals from within the cell (Intracellular)
the rate of a metabolic pathway may respond to regulatory signals
from the cell, e.g. the rate of the pathway may be influenced by the
availability of the substrate, product inhibition or alterations in the
level of allosteric activators or inhibitors. These intracellular signals
provide rapid responses and are important for the moment to moment
regulation metabolism
*Communication between cells.
Signals between cells provide for long-range integration of metabolism
and show slower response. Cell communication involves surface
interactions. For metabolism the chemical signaling is involved like
hormones and neurotransmitters released by nervous system
Biosignaling: Signal transduction
Signal transduction is specific and very sensitive
* Specificity is achieved by precise molecular complementary between
signal and receptor molecule.
Epinephrine affect glycogen metabolism in hepatocyet and not in
erythrocyte because of the absence of the receptors.
The affinity of the signal to the receptor is very high
Two Basic mechanisms of Signal transduction
Intracellular receptors
Cell-surface receptors
highly sensitive
Transduction by intracellular receptors
Vit D, steroidal hormones, retinoic acid and
thyroxine act through intracellular
receptors located in the cytosol or the
nucleus. The receptor-ligand complex inter
the nucleus and bind to specific regions of
the DNA (enhancer region) causing
increasing the expression of the specified
gene. These hormones should penetrate the
cell membrane and bind to specific region.
Their effect are not immediate because
time is required for gene transcription and
then mRNA translation. But the duration of
action will be longer.
steroid
c
Transduction by cell-surface receptors.
• Signals transduction by hormones and neurotransmitters is
initiated by ligand binding to receptors located in the plasma
membrane.
• This transduction dose not regulate the gene expression
directly. Simply signal interact with receptors  activated
receptors interact with cellular machinery producing a second
signal or change in the activity of a cellular protein  metabolic
change in target
Three general classes of cell-surface receptors based on their
mechanism of signal transduction.
a. Ligand-Gated Ion channels (Neurotransmitter receptors linked
to ion channels).
b. Receptor enzyme (Catalytic receptors)
c. Receptors involving second messenger molecules.
Three general classes of cell-surface receptors based on their
mechanism of signal transduction
Ligand-Gated Ion channels
Commonly called transmitter-gated ion channels or ionotropic receptors
-
Involved in rapid synaptic signaling
Best example for this type is Nicotinic acetylcholine receptors
-
Acetylcholine receptors are allosteric protein with two binding sites for Ach.
-
Classically defined by acetylcholine (ACh) receptor at neuromuscular junction
-
Nerve impulse depolarize axon, signal travels to nerve terminal leading to
opening of voltage-gated Ca+ channels, Ca+ flows in and Ach is released to
post synaptic neuron or myocyte.
-
Ach binds receptors on muscle cells leading to opening of cation (Ca+, Na+)
channel and Na+ flows in and thus depolarization of the receiving cell
initiates another action potential (neuron) or contraction of the muscle cell (if
myocyte)
Voltage-Gated Ion channels open and close as response to electrical change
Voltage-gated Na+ channel
Voltage-gated K+ channel
Voltage-gated Ca+ channel
figure 13-5
Role of voltage-gated and ligand-gated ion channels
in neural transmission. Initially, the plasma membrane
of the presynaptic neuron IS polarized (inside negative)
through the action of the electrogenic Na+-K+ ATPase.
which pumps 3 Na+ out for every 2 K+ pumped Into the
neuron , (1) A stimulus to this neuron causes an action
potential to move along the axon (white arrow), away
from the cell body. The opening of one voltage-gated
Na+ channel allows Na+ entry and the resulting local
depolarization causes the adjacent Na+ channel to open,
and so on. The directionality of movement of the action
potential is ensured by the brief refractory period that
follows the opening of each voltage-gated Na+ channel.
(2) When the wave of depolarization reaches the axon
tip, voltage-gated Ca+2 channels open, allowing Ca+2
entry into the presynaptic neuron. (3) The resulting
increase in internal [Ca+2] triggers exocytic release of
the neurotransmitter acetyleholme into the
synaptic cleft. (4) Acetylcholine binds to a receptor on
the postsynaptic neuron, causing its ligand-gated Ion
channel to open. (5) Extracellular Na+ and Ca++ enter
through this channel, depolarizing the postsynaptic cell.
The electrical signal has thus passed to the cell body
of the postsynaptic neuron and will move along its axon
to a third neuron by the same sequence of events.
Ach binds receptors on muscle cells leading to opening of cation (Ca+, Na+)
channel and Na+ flows in and thus depolarization of the receiving cell
initiates
another action potential (neuron) or contraction of the muscle cell (if
myocyte)
Neural transmission
Receptor Enzyme
•These Transmembrane catalytic receptors have an
inherent enzymatic activity as part of their structure.
• have ligand binding domain on the extracellular surface
of the plasma membrane and enzyme active site on the
cytosolic side.
• Commonly they are a protein kinase that phosphorlate
Tyr residues in the specific target proteins
• Insulin receptor is prototype for this type
• The binding of the a ligand (insulin) to its receptor
activates the tyrosine kinase activity which transfer the
phosphate group from ATP to the –OH group of the Tyr
residues of target proteins and of the receptor itself
figure 13-6
Insulin receptor. The insulin
receptor consists of two
α chains on the outer face of the
plasma membrane and two  chains
that traverse tile membrane and
protrude from the cytosolic face.
Binding of insulin to the α chains
triggers a conformational change
that allows the autophosphorylation
of Tyr residues in the carboxylterminal domain of the  subunits.
Autopllosphorylation further
activates the tyrosine kinase
domain, which then catalvzes
phosphorvlation of other target
proteins.
Receptors involving second messenger molecules.
Many signals when bind to their receptors initiate a series of reactions in
form of cascade reactions that at the end result in a specific
intracellular response. The intracellular messenger systems function as
signal amplification.
signal amplification.
Receptors involving second messenger molecules
I. Adenylate cyclase system
-Typical example is the adrenergic receptors β-receptors that bind to
epinephrine and then trigger either an increase or decrease in the activity of
the adenylate cyclase.
- Adenylate cyclase convert the ATP into cAMP which act as second
messenger and activate other enzymes to produce the activity.
- Many signals (hormones) act through activating the cAMP like glucagon
- the effect of signals on the second messenger is not direct but mediated
through G-proteins. GTP-dependent regulatory proteins. The inactive form of
G-protein binds to GDP while the active form bind to GTP.
- The binding of hormone to its receptor activate the G-protein which affect
the activity of adenylate cyclase
- The activity of signal depends one the type of G-proteins. Gs stimulates the
adenylate cyclase while Gi inhibits it.
- The actions of G-protein _GTP complex are short lived because G-protein
has an inherent GTPase activity, resulting in rapid hydrolysis of GTP to GDP
and this causes the inactivation of G-protein.
Adenylate cyclase convert the ATP into cAMP
which act as second messenger
Receptors involving second
messenger molecules
Adenylate cyclase system
Role of G-Proteins in Signal Transduction
Activation Adenylate cyclase system via G-Proteins
cAMP activates Protein Kinases A.
-The next link in the cAMP second messenger system is the activation of Protein
Kinases by cAMP.
- Family of enzymes called cAMP-dependent protein kinases.
- Protein Kinase A is the typical example, consists of 4 monomers. 2 catlytics and
2 regulatory.
-The active subunits catalyze the transfer of phosphate from ATP to specific
serine or threonine residues of protein substrate.
- the phosphorylated protein can act directly or can activate or inhibit other
enzymes to produce the effect.
- Not all protein kinases respond to cAMP, other types are cAMP-independent
protein kinase like proetin kinase C.
- The phosphate group can be removed by proetin phosphatases.
- cAMP is rapidly hydrolyzed to 5-AMP by phosphodiesterase.
Activation of
cAMP-dependent
protein kinase,
PKA
Activation of cAMPdependent protein kinase
(PKA)
Phosphatidylinositol 4,5 bisphosphate
Two second messengers derived from Phosphatidylinositol
IP3
Second messengers derived from
Phosphatidylinositol
Role of Phosphatidylinositol 4,5 bisphosphate in
Signal transduction
IP3 activates the release of Ca+
Ca+ is a second messenger in many signal
transductions
-Ca+ serves as a second messenger that triggers
intracellular responses as exocytosis in neurons
and endocrine cells, contraction in muscle and
others
- Ca+ is released from endoplasmic reticulum in
response to signals (hormones,
neurotransmitters)
- Ca+ bind to Ca-binding proteins that called
calmodulin
- Calmodulin-ca complex binds and activates
protein molecules usually enzymes,
- Calmodulin is regulatory subunit of
phosphorylase b kinase of muscle that activated
by Ca  activating the break down of glycogen.
- Many enzymes are know to be modulated by
Ca+ through calmodulin.
Ca+ is a second messenger in many signal transductions
Other messenger systems
a. cGMP
b. Nitric oxide
* Cyclic guanosine monophosphate
It is analogous to cAMP pathway
Synthesized from GTP by guanylate cyclase, it an integral part of
the receptor (not separated like Adenylate cyclase), it contains
heme as prosthetic group and stimulated by nitric oxide.
Activate a spcific form of protein kinase called cGMP-dependent
protein kinase also called protein kinase G
cGMP is hydrolyzed by phosphodiesterase
cGMP is a specialized messenger being involved in smooth muscle
relaxation, platelet aggregation and the visual system. cAMP
affects a wide variety of processes.
Nitric Oxide
NO act as endothelium relaxing factor, causes vasodilatation by relaxing vascular
smooth muscle and also acts as neurotransmitters, prevents platelet aggregation
and has a role in macrophage function.
It is highly toxic. Nitrous oxide ( NO2) the “ laughing gas” that used as
anesthetic.
NO is very short lived and unstable converted into oxygen and nitrate and
nitrite.
Synthesis of NO
-NO synthase catalyzes the formation of NO from amino acid Arginine, FMN,
FAD, and tetrahydrobiopterin are coenzymes for the enzymes
- NO is synthesized in endothelial cells and diffuses to vascular smooth muscle
activate the guanylate cyclase  rise in cGMP which causes muscle relaxation.
- Synthesis of NO is stimulated in the macrophages by bacterial
liopolysaccharides  activated macrophages form oxygen free radical that
combine with NO to form compounds that are more bactericidal than NO itself
Nitric Oxide act as
endothelium relaxing factor,
causes vasodilatation by
relaxing vascular smooth muscle
and also acts as
neurotransmitters, prevents
platelet aggregation and many
functions