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CELL SIGNALING
Submitted By-
Shruti Rajeev Gautam
(M.Pharma 1th year )
Guide-
Prof Mrs Anjali . Wankhade
Vidya Bharati College of Pharmacy, Amravati.
2019-2020
INDEX
 Introduction
 Intercellular and intracellular signaling
 Receptor
 Secondary messenger
 Reference
INTRODUCTION
 Cell signaling is part of any communication process that
governs basic activities of cells and coordinates multiple-
cell actions.
 The ability of cells to perceive and correctly respond to
their microenvironment is the basis of development,
tissue repair, and immunity, as well as normal tissue
homeostasis.
 Errors in signaling interactions and cellular information
processing may cause diseases such as cancer,
autoimmunity, and diabetes
CLASSIFICATION
 Cell signaling can be classified as either mechanical or
biochemical based on the type of the signal.
 Mechanical signals are the forces exerted on the cell and
the forces produced by the cell. These forces can both be
sensed and responded to by the cells.
 Biochemical signals are the biochemical molecules such
as proteins, lipids, ions and gases.
INTERCELLULAR SIGNALING
 Intercellular signal transduction influences nearly every
physiological reaction. It ensures that all cells of a
particular type receive and transform a signal.
 In this manner, cells of the same type react
synchronously to a signal. A further function of
intercellular communication is the coordination of
metabolite fluxes between cells of various tissues.
 In higher organisms intercellular signaling pathways
have the important task of coordinating and regulating
cell division. The pathways ensure that cells divide
synchronously and, if necessary, arrest cell division and
enter a resting state.
INTRACELLULAR SIGNALING
 External signals such as hormones or sensory signals are
specifically recognized by receptors that transduce the
external signal into an intracellular signaling chain.
 The intracellular signaling paths control all functions of
the cell such as intermediary metabolism, cell division
activity, morphology and the transcription programe.
RECEPTOR
 Receptor are the sensing element in the system of
chemical communication that coordinates the function of
all the different cell in the body the chemical messenger
being the various hormone, transmitter & other mediator
 Many therapeutically useful drug act either as antagonist
or agonist on receptor for know endogenous mediator
TYPE OF RECEPTOR
 Receptor elicit many different type of cellular effect
 Some of them are very rapid such as those involved in
synaptic transmission ,operating within millisecond
where as other receptor mediated effect such as those
produced by thyroid hormone or various steroid
hormones occur over hour or day
 Based on molecular structure and the nature of this
linkage
a) Ligand gate ion channel
b) G protein coupled receptor
c) Kinase linked receptor
d) Nuclear receptor
LIGAND GATE ION CHANNEL
 It is also know as inotropic receptor
 a group of trans membrane ion-channel proteins which
open to allow ions such as 𝑁𝑎+
, 𝐾+
, 𝐶𝑎2+
, and 𝐶𝑙−
to
pass through the membrane in response to the binding of
a chemical messenger (i.e. a ligand), such as a
neurotransmitter.
 These are the receptor on which fast neurotransmitter act
 Ligand binding and channel opening occur on a
millisecond timescale
 Example include the nicotine acetylcholine receptor ,
GABA receptor , 5 hydroxytryptamine type 3 receptor
MOLECULAR STRUCTURE
 The nicotine acetylcholine receptor the first to be cloned
 It consist of pentameric assembly of different subunit of
which these are four type termed α, β,γ, δ
 Molecular weight 40-50 Kda
 The pentameric structure possess two acetylcholine
binding site each lying at interface between one of the
subunit and its neighbor
 Both must bind acetylcholine molecule in order for the
receptor to be activate
 Each subunit span the membrane four time so the
channel comprise no fewer then 20 membrane spanning
a central pores
G PROTEIN COUPLED RECEPTOR
 G protein-coupled receptors (GPCRs), also known as seven-
(pass)-transmembrane domain receptors, 7TM receptors,
heptahelical receptors, serpentine receptor, and G protein–
linked receptors (GPLR), constitute a large protein family of
receptors that detect molecules outside the cell and activate
internal signal transduction pathways and, ultimately, cellular
responses. Coupling with G proteins, they are called seven-
transmembrane receptors because they pass through the cell
membrane seven times.
 G protein-coupled receptors are found only in eukaryotes,
including yeast, choanoflagellates ,and animals.
 G protein-coupled receptors are involved in many diseases.
MOLECULAR STRUCTURE
 G protein coupled receptor consist of a single
polypeptide chain of up to 1100
 Their characteristic structure comprise seven trans
membrane α helices
 G protein coupled receptor are divided into three distinct
families
 They share the same seven helix structure but differ in
other principally in the length of the extracellular N
terminal and the location of the agonist binding domain
Family Receptor Structural
feature
A: rhodospin family The largest group
receptor for most amine
neurotransmitter many
neuropeptide purine
,prostanoid ,cannabinoids
Short extracellular tail
ligand bind to trans
membrane helices or to
extracellular loops
B: secretin/glucagon
receptor family
Receptor for peptide
hormones including
secretin ,glucagon,
calcitonin
Intermediate extra cellar
tail incorporating ligand
binding domain
C: metabotropic
glutamate receptor
/calcium sensor family
Small group metabotropic
glutamate receptor ,
GAB 𝐴 𝐵 receptor, 𝐶𝑎2+
sensing receptor
Long extracellular tail
incorporating ligand
binding domain
G PROTEIN AND THEIR ROLE
 G Protein comprise a family of membrane resident
protein whose function is to recognize activated GPCRs
and pass on the message to the effector system that
generate a cellular response
 They represent the level of middle management in the
organizational hierarchy intervening between the
receptor –choosy mandarin alert to the faintest whiff of
their preferred chemical – and effector enzymes or ion
channel – the blue collar brigade that get the job done
without needing to know which hormones authorized the
process
KINASE LINKED AND RELATED RECEPTOR
 These membrane receptor are quite different in structure
and function from either the ligand gate channel or the
GPCRs
 They mediate the action of wide variety of protein
mediator including growth factor and cytokines and
hormones such as insulin whose effect are exerted
mainly at the level of gene transcription
 Most of these receptor are large chain protein consisting
of single chain of up to 1000 residue with single
membrane spanning helical region associated with a
large extracellular ligand binding domain and an
intracellular domain of variable size and function
 The main type are as follow
1) Receptor tyrosine kinase
2) Serine/ threonine kinase
3) Cytokinse receptor
1. Receptor tyrosine kinase
 These receptor have the basic structure incorporating a
tyrosin kinase moiety in the intracellular region they
include receptor for many growth factor such as
epidermal growth factor and nerve factor and also the
group of toll- like receptor that recognize bacterial
lipopolysaccaride and play important role in the body
reaction to infection . The insulin receptor also belong to
the RTK class although it has a more complex domain
2. Serine/ threonine kinase
 This smaller class is similar in structure to RTK but
phosphorylate serine and threonine residue rather than
tyrosine. The main example is the receptor for
transforming growth factor (TGF)
3. Cytokinase receptor
 These receptor lack enzyme activity . When occupied
they associate with activate a cytosolic tyrosine kinase
such as Jak or other kinase . Ligand for these receptor
include cytokinase such as interferon's and colony-
stimulating factor involved in immunological reponses
NUCLEAR RECEPTOR
 The fourth type of receptor belong to the nuclear
receptor family
 By the 1970 it was clear that receptor for steroid
hormone such estrogen and the glucocorticoid were
present in the cytoplasm of cell and translocate into the
nucleus after binding with their steroid partner
 Other hormones such as the thyroid hormone and fat
soluble vitamin D and A were found to act in a similar
fashion
 NRs such as the glucocorticoid and retinoic acid receptor
whose ligand were well characterized this family include
a great many orphan receptor
SECONDARY MESSENGER
 Secondary messenger are intercellular signaling molecule released
by the cell to trigger physiological change such as proliferation ,
Differentiation ,migration , survival and apopties
 Secondary messenger are therefore one of the initiating component
of intracellular signal transduction cascade
 Example of secondary messenger include cyclic AMP, cyclic GMP,
calcium ion , inositol 1,4,5- trisphosphate and diacylglycerol
CYCLIC AMP
 Cyclic adenosine 3′,5′-monophosphate (cAMP) was the
first second messenger to be identified and plays
fundamental roles in cellular responses to many
hormones and neurotransmitters .
 The intracellular levels of cAMP are regulated by the
balance between the activities of two enzymes : adenylyl
cyclase (AC) and cyclic nucleotide phosphodiesterase
(PDE).
 Different isoforms of these enzymes are encoded by a
large number of genes, which differ in their expression
patterns and mechanisms of regulation, generating cell-
type and stimulus-specific responses
CYCLIC GMP
 Cyclic guanosine monophosphate (cGMP) is a cyclic
nucleotide derived from guanosine triphosphate (GTP).
 cGMP acts as a second messenger much like cyclic
AMP. Its most likely mechanism of action is activation
of intracellular protein kinases in response to the binding
of membrane-impermeable peptide hormones to the
external cell surface
INOSITOL 1,4,5-TRISPHOSPHATE
 inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P
or IP3 is an inositol phosphate signaling molecule.
 It is made by hydrolysis of phosphatidylinositol 4,5-
bisphosphate (PIP2), a phospholipid that is located in the
plasma membrane, by phospholipase C (PLC).
 Together with diacylglycerol (DAG), IP3 is a second
messenger molecule used in signal transduction in
biological cells.
 While DAG stays inside the membrane, IP3 is soluble
and diffuses through the cell, where it binds to its
receptor, which is a calcium channel located in the
endoplasmic reticulum. .
SIGNALING PATHWAY
 Increases in the intracellular 𝐶𝑎2+ concentrations are
often a result of IP3 activation. When a ligand binds to a
G protein-coupled receptor (GPCR) that is coupled to a
Gq heterotrimeric G protein, the α-subunit of Gq can
bind to and induce activity in the PLC isozyme PLC-β,
which results in the cleavage of PIP2 into IP3 and DAG.
 If a receptor tyrosine kinase (RTK) is involved in
activating the pathway, the isozyme PLC-γ has tyrosine
residues that can become phosphorylated upon activation
of an RTK, and this will activate PLC-γ and allow it to
cleave PIP2 into DAG and IP3. This occurs in cells that
are capable of responding to growth factors such as
insulin, because the growth factors are the ligands
responsible for activating the RTK.
 IP3 is a soluble molecule and is capable of
diffusing through the cytoplasm to the ER, or the
sarcoplasmic reticulum (SR) in the case of
muscle cells, once it has been produced by the
action of PLC. Once at the ER, IP3 is able to
bind to the IIns(1,4,5)P3 receptor Ins(1,4,5)P3R
on a ligand-gated 𝐶𝑎2+ channel that is found on
the surface of the ER.
 The binding of IP3 to Ins(1,4,5)P3R triggers the
opening of the 𝐶𝑎2+
channel, and thus release of
𝐶𝑎2+
into the cytoplasm.
DIACYLGLYCEROL
 A diglyceride, or diacylglycerol (DAG), is a glyceride
consisting of two fatty acid chains covalently bonded to a
glycerol molecule through ester linkages. Two possible
forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols
PROTEIN KINASE C ACTIVATION
 In biochemical signaling, diacylglycerol functions as a
second messenger signaling lipid, and is a product of the
hydrolysis of the phospholipid phosphatidylinositol 4,5-
bisphosphate (PIP2) by the enzyme phospholipase C
(PLC) (a membrane-bound enzyme) that, through the
same reaction, produces inositol trisphosphate (IP3).
 Although inositol trisphosphate diffuses into the cytosol,
diacylglycerol remains within the plasma membrane, due
to its hydrophobic properties.
 IP3 stimulates the release of calcium ions from the
smooth endoplasmic reticulum, whereas DAG is a
physiological activator of protein kinase C (PKC).
membrane.
MUNC13 ACTIVATION
 Diacylglycerol has been shown to exert some of its
excitatory actions on vesicle release through
interactions with the presynaptic priming protein
family Munc13. Binding of DAG to the C1 domain of
Munc13 increases the fusion competence of
synaptic vesicles resulting in potentiated release.
 Diacylglycerol can be mimicked by the tumor-
promoting compounds phorbol esters
REFERENCE
 Rang and Dale's Pharmacology-James Ritter, Rod J.
Flower, G. Henderson, David J. MacEwan, Yoon Kong
Loke, H. P. Rang
 Basic & Clinical Pharmacology- Katzung and Bertram

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Cell signaling

  • 1. CELL SIGNALING Submitted By- Shruti Rajeev Gautam (M.Pharma 1th year ) Guide- Prof Mrs Anjali . Wankhade Vidya Bharati College of Pharmacy, Amravati. 2019-2020
  • 2. INDEX  Introduction  Intercellular and intracellular signaling  Receptor  Secondary messenger  Reference
  • 3. INTRODUCTION  Cell signaling is part of any communication process that governs basic activities of cells and coordinates multiple- cell actions.  The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity, as well as normal tissue homeostasis.  Errors in signaling interactions and cellular information processing may cause diseases such as cancer, autoimmunity, and diabetes
  • 4. CLASSIFICATION  Cell signaling can be classified as either mechanical or biochemical based on the type of the signal.  Mechanical signals are the forces exerted on the cell and the forces produced by the cell. These forces can both be sensed and responded to by the cells.  Biochemical signals are the biochemical molecules such as proteins, lipids, ions and gases.
  • 5. INTERCELLULAR SIGNALING  Intercellular signal transduction influences nearly every physiological reaction. It ensures that all cells of a particular type receive and transform a signal.  In this manner, cells of the same type react synchronously to a signal. A further function of intercellular communication is the coordination of metabolite fluxes between cells of various tissues.  In higher organisms intercellular signaling pathways have the important task of coordinating and regulating cell division. The pathways ensure that cells divide synchronously and, if necessary, arrest cell division and enter a resting state.
  • 6. INTRACELLULAR SIGNALING  External signals such as hormones or sensory signals are specifically recognized by receptors that transduce the external signal into an intracellular signaling chain.  The intracellular signaling paths control all functions of the cell such as intermediary metabolism, cell division activity, morphology and the transcription programe.
  • 7.
  • 8. RECEPTOR  Receptor are the sensing element in the system of chemical communication that coordinates the function of all the different cell in the body the chemical messenger being the various hormone, transmitter & other mediator  Many therapeutically useful drug act either as antagonist or agonist on receptor for know endogenous mediator
  • 9. TYPE OF RECEPTOR  Receptor elicit many different type of cellular effect  Some of them are very rapid such as those involved in synaptic transmission ,operating within millisecond where as other receptor mediated effect such as those produced by thyroid hormone or various steroid hormones occur over hour or day  Based on molecular structure and the nature of this linkage a) Ligand gate ion channel b) G protein coupled receptor c) Kinase linked receptor d) Nuclear receptor
  • 10. LIGAND GATE ION CHANNEL  It is also know as inotropic receptor  a group of trans membrane ion-channel proteins which open to allow ions such as 𝑁𝑎+ , 𝐾+ , 𝐶𝑎2+ , and 𝐶𝑙− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.  These are the receptor on which fast neurotransmitter act  Ligand binding and channel opening occur on a millisecond timescale  Example include the nicotine acetylcholine receptor , GABA receptor , 5 hydroxytryptamine type 3 receptor
  • 11. MOLECULAR STRUCTURE  The nicotine acetylcholine receptor the first to be cloned  It consist of pentameric assembly of different subunit of which these are four type termed α, β,γ, δ  Molecular weight 40-50 Kda  The pentameric structure possess two acetylcholine binding site each lying at interface between one of the subunit and its neighbor  Both must bind acetylcholine molecule in order for the receptor to be activate  Each subunit span the membrane four time so the channel comprise no fewer then 20 membrane spanning a central pores
  • 12.
  • 13. G PROTEIN COUPLED RECEPTOR  G protein-coupled receptors (GPCRs), also known as seven- (pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein– linked receptors (GPLR), constitute a large protein family of receptors that detect molecules outside the cell and activate internal signal transduction pathways and, ultimately, cellular responses. Coupling with G proteins, they are called seven- transmembrane receptors because they pass through the cell membrane seven times.  G protein-coupled receptors are found only in eukaryotes, including yeast, choanoflagellates ,and animals.  G protein-coupled receptors are involved in many diseases.
  • 14.
  • 15. MOLECULAR STRUCTURE  G protein coupled receptor consist of a single polypeptide chain of up to 1100  Their characteristic structure comprise seven trans membrane α helices  G protein coupled receptor are divided into three distinct families  They share the same seven helix structure but differ in other principally in the length of the extracellular N terminal and the location of the agonist binding domain
  • 16. Family Receptor Structural feature A: rhodospin family The largest group receptor for most amine neurotransmitter many neuropeptide purine ,prostanoid ,cannabinoids Short extracellular tail ligand bind to trans membrane helices or to extracellular loops B: secretin/glucagon receptor family Receptor for peptide hormones including secretin ,glucagon, calcitonin Intermediate extra cellar tail incorporating ligand binding domain C: metabotropic glutamate receptor /calcium sensor family Small group metabotropic glutamate receptor , GAB 𝐴 𝐵 receptor, 𝐶𝑎2+ sensing receptor Long extracellular tail incorporating ligand binding domain
  • 17. G PROTEIN AND THEIR ROLE  G Protein comprise a family of membrane resident protein whose function is to recognize activated GPCRs and pass on the message to the effector system that generate a cellular response  They represent the level of middle management in the organizational hierarchy intervening between the receptor –choosy mandarin alert to the faintest whiff of their preferred chemical – and effector enzymes or ion channel – the blue collar brigade that get the job done without needing to know which hormones authorized the process
  • 18. KINASE LINKED AND RELATED RECEPTOR  These membrane receptor are quite different in structure and function from either the ligand gate channel or the GPCRs  They mediate the action of wide variety of protein mediator including growth factor and cytokines and hormones such as insulin whose effect are exerted mainly at the level of gene transcription  Most of these receptor are large chain protein consisting of single chain of up to 1000 residue with single membrane spanning helical region associated with a large extracellular ligand binding domain and an intracellular domain of variable size and function
  • 19.  The main type are as follow 1) Receptor tyrosine kinase 2) Serine/ threonine kinase 3) Cytokinse receptor 1. Receptor tyrosine kinase  These receptor have the basic structure incorporating a tyrosin kinase moiety in the intracellular region they include receptor for many growth factor such as epidermal growth factor and nerve factor and also the group of toll- like receptor that recognize bacterial lipopolysaccaride and play important role in the body reaction to infection . The insulin receptor also belong to the RTK class although it has a more complex domain
  • 20. 2. Serine/ threonine kinase  This smaller class is similar in structure to RTK but phosphorylate serine and threonine residue rather than tyrosine. The main example is the receptor for transforming growth factor (TGF) 3. Cytokinase receptor  These receptor lack enzyme activity . When occupied they associate with activate a cytosolic tyrosine kinase such as Jak or other kinase . Ligand for these receptor include cytokinase such as interferon's and colony- stimulating factor involved in immunological reponses
  • 21.
  • 22. NUCLEAR RECEPTOR  The fourth type of receptor belong to the nuclear receptor family  By the 1970 it was clear that receptor for steroid hormone such estrogen and the glucocorticoid were present in the cytoplasm of cell and translocate into the nucleus after binding with their steroid partner  Other hormones such as the thyroid hormone and fat soluble vitamin D and A were found to act in a similar fashion  NRs such as the glucocorticoid and retinoic acid receptor whose ligand were well characterized this family include a great many orphan receptor
  • 23.
  • 24. SECONDARY MESSENGER  Secondary messenger are intercellular signaling molecule released by the cell to trigger physiological change such as proliferation , Differentiation ,migration , survival and apopties  Secondary messenger are therefore one of the initiating component of intracellular signal transduction cascade  Example of secondary messenger include cyclic AMP, cyclic GMP, calcium ion , inositol 1,4,5- trisphosphate and diacylglycerol
  • 25. CYCLIC AMP  Cyclic adenosine 3′,5′-monophosphate (cAMP) was the first second messenger to be identified and plays fundamental roles in cellular responses to many hormones and neurotransmitters .  The intracellular levels of cAMP are regulated by the balance between the activities of two enzymes : adenylyl cyclase (AC) and cyclic nucleotide phosphodiesterase (PDE).  Different isoforms of these enzymes are encoded by a large number of genes, which differ in their expression patterns and mechanisms of regulation, generating cell- type and stimulus-specific responses
  • 26. CYCLIC GMP  Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP).  cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in response to the binding of membrane-impermeable peptide hormones to the external cell surface
  • 27. INOSITOL 1,4,5-TRISPHOSPHATE  inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule.  It is made by hydrolysis of phosphatidylinositol 4,5- bisphosphate (PIP2), a phospholipid that is located in the plasma membrane, by phospholipase C (PLC).  Together with diacylglycerol (DAG), IP3 is a second messenger molecule used in signal transduction in biological cells.  While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell, where it binds to its receptor, which is a calcium channel located in the endoplasmic reticulum. .
  • 28. SIGNALING PATHWAY  Increases in the intracellular 𝐶𝑎2+ concentrations are often a result of IP3 activation. When a ligand binds to a G protein-coupled receptor (GPCR) that is coupled to a Gq heterotrimeric G protein, the α-subunit of Gq can bind to and induce activity in the PLC isozyme PLC-β, which results in the cleavage of PIP2 into IP3 and DAG.  If a receptor tyrosine kinase (RTK) is involved in activating the pathway, the isozyme PLC-γ has tyrosine residues that can become phosphorylated upon activation of an RTK, and this will activate PLC-γ and allow it to cleave PIP2 into DAG and IP3. This occurs in cells that are capable of responding to growth factors such as insulin, because the growth factors are the ligands responsible for activating the RTK.
  • 29.  IP3 is a soluble molecule and is capable of diffusing through the cytoplasm to the ER, or the sarcoplasmic reticulum (SR) in the case of muscle cells, once it has been produced by the action of PLC. Once at the ER, IP3 is able to bind to the IIns(1,4,5)P3 receptor Ins(1,4,5)P3R on a ligand-gated 𝐶𝑎2+ channel that is found on the surface of the ER.  The binding of IP3 to Ins(1,4,5)P3R triggers the opening of the 𝐶𝑎2+ channel, and thus release of 𝐶𝑎2+ into the cytoplasm.
  • 30.
  • 31. DIACYLGLYCEROL  A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols
  • 32. PROTEIN KINASE C ACTIVATION  In biochemical signaling, diacylglycerol functions as a second messenger signaling lipid, and is a product of the hydrolysis of the phospholipid phosphatidylinositol 4,5- bisphosphate (PIP2) by the enzyme phospholipase C (PLC) (a membrane-bound enzyme) that, through the same reaction, produces inositol trisphosphate (IP3).  Although inositol trisphosphate diffuses into the cytosol, diacylglycerol remains within the plasma membrane, due to its hydrophobic properties.  IP3 stimulates the release of calcium ions from the smooth endoplasmic reticulum, whereas DAG is a physiological activator of protein kinase C (PKC). membrane.
  • 33. MUNC13 ACTIVATION  Diacylglycerol has been shown to exert some of its excitatory actions on vesicle release through interactions with the presynaptic priming protein family Munc13. Binding of DAG to the C1 domain of Munc13 increases the fusion competence of synaptic vesicles resulting in potentiated release.  Diacylglycerol can be mimicked by the tumor- promoting compounds phorbol esters
  • 34. REFERENCE  Rang and Dale's Pharmacology-James Ritter, Rod J. Flower, G. Henderson, David J. MacEwan, Yoon Kong Loke, H. P. Rang  Basic & Clinical Pharmacology- Katzung and Bertram