Intracellular Signaling Flashcards
Cell Communication
•Each cell in a ____ ____ has been programmed to respond to specific ____ signals produced by other cells or the environment. These signals act in various combinations to regulate the _____ of the cell.
•Communication by extracellular signals usually involves a series of events:
1.____ of _____ ___ ____ in response to a ____
2.___ of the chemical messenger by the ____ cell
3.____ of the chemical messenger to the ___ cell
4.____ of the chemical messenger by a specific___ ____
5.___of an ___ ____ by the ___-___ ____(sometimes, the receptor is the ____)
6.____ in cellular ____ producing ____ ___ ___s, ___n, or ____ triggered by the effector
7____ through changes in protein ____ that could lead to changes in ___ and ___
8_____of the signal, which often____ the cellular response.
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•Each cell in a multicellular animal has been programmed to respond to specific extracellular signals produced by other cells or the environment. These signals act in various combinations to regulate the behavior of the cell.
•Communication by extracellular signals usually involves a series of events:
1.Synthesis of extracellular chemical messenger in response to a stimulus
2.Release of the chemical messenger by the signaling cell
3.Transport of the chemical messenger to the target cell
4.Binding of the chemical messenger by a specific receptor protein
5.Activation of an effector protein by the messenger-receptor complex (sometimes, the receptor is the effector)
6.Change in cellular metabolism producing intracellular second messengers, function, or transcription triggered by the effector
7.Response through changes in protein function that could lead to changes in transcription and translation
8.Removal of the signal, which often terminates the cellular response.
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Extracellular (____) Chemical Messengers/____/Signaling Molecules
•A few examples of chemical messengers are
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____
___ ___
•General features of chemical messengers are
- They secreted by ____ cells in response to a ____
- The messenger ____ or is____ Through blood/other extracellular fluid to the ____ cell
- A receptor in the target cell ____ binds the messenger
- Binding of messenger to receptor elicits a _____
- The signal ___-and is terminated
•A few examples of chemical messengers are
- Neutrotransmitters
- Hormones
- Cytokines
- Growth factors
•General features of chemical messengers are
- They secreted by specific cells in response to a stimulus
- The messenger diffuses or is transported through blood/other extracellular fluid to the target cell
- A receptor in the target cell specifically binds the messenger
- Binding of messenger to receptor elicits a response
- The signal ceases and is terminated
Relationship between messenger producing cell and the target cell
A.Endocrine signaling – The chemical messenger (____) is secreted by a ____Cell type (_____ne ___), _____s the ____, which carries the signal to target cells distributed____ throughout the body.
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B.Paracrine signaling – The chemical messenger secreted acts on ____ target cells. The secreted molecules are not allowed to __ ___ ___; for this reason they are often ___ ____up by ____target cells, ____ by extracellular enzymes. Ex-_____
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C.Autocrine signaling – The chemical messenger acts on the cells from which it is ____. Ex – cellular _____ during ____t,
_____r cells often use autocrine signaling to overcome the normal controls on cell ___ and ____
A.Endocrine signaling – The chemical messenger (hormone) is secreted by a specific cell type (endocrine gland), enters the blood, which carries the signal to target cells distributed widely throughout the body.
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B.Paracrine signaling – The chemical messenger secreted acts on nearby target cells. The secreted molecules are not allowed to diffuse too far; for this reason they are often rapidly taken up by neighboring target cells, destroyed by extracellular enzymes. Ex-neurotransmission.
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C.Autocrine signaling – The chemical messenger acts on the cells from which it is secreted. Ex – cellular differentiation during development, cancer cells often use autocrine signaling to overcome the normal controls on cell proliferation and survival.
Note - Not all extracellular messengers are secreted
Contact-dependent signaling
Many signal molecules ___ ___ to the surface of the signaling cell and influence only cells that contact it. Such contact-dependent signaling is especially important ___ ____t and in ___ ____
Gap Junctions
Specialized cell-cell junctions that form between closely apposed plasma membranes and directly connect the____ of the joined cells via narrow _____- ____ channels. The channels allow the exchange of ___ _____ signaling molecules. Thus, cells connected by gap junctions can communicate with each other ___
Many signal molecules remain bound to the surface of the signaling cell and influence only cells that contact it. Such contact-dependent signaling is especially important during development and in immune responses.
Specialized cell-cell junctions that form between closely apposed plasma membranes and directly connect the cytoplasms of the joined cells via narrow water-filled channels. The channels allow the exchange of small intracellular signaling molecules. Thus, cells connected by gap junctions can communicate with each other directly.
Receptors
•Cellular response to a particular extracellular signaling molecule depends on its binding to a ____ receptor protein located on the surface of a t___ ____ (Cell surface receptors) or in its ___ or ____(Intracellular receptors).
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•Binding of a signaling molecule (ligand) to its receptor is _____e, ie, the ligand “___,” a site on the receptor – similar to “lock and key mechanism” of enzyme-substrate reaction.
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•Binding of a ligand to its receptor causes a _____ change in the receptor that initiates a ___ of ____leading to a specific cellular_____
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•Signaling is specific because
- Typically ___ receptor binds only ___ specific messenger
- Only certain cells (target cells) carry ____ for the ____
- Each receptor initiates a characteristic ___ ___ ___.
•The extracellular messenger (ligand) is not metabolized to useful products, is not an intermediate in any cellular activity, and has no enzymatic properties. The only function of the ligand appears to be to change the properties of the receptor.
•Cellular response to a particular extracellular signaling molecule depends on its binding to a specific receptor protein located on the surface of a target cell (Cell surface receptors) or in its cytosol or nucleus (Intracellular receptors).
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•Binding of a signaling molecule (ligand) to its receptor is selective, ie, the ligand “fits,” a site on the receptor – similar to “lock and key mechanism” of enzyme-substrate reaction.
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•Binding of a ligand to its receptor causes a conformational change in the receptor that initiates a sequence of reactions leading to a specific cellular response.
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•Signaling is specific because
- Typically one receptor binds only one specific messenger
- Only certain cells (target cells) carry receptors for the messenger
- Each receptor initiates a characteristic signal transduction pathway
•The extracellular messenger (ligand) is not metabolized to useful products, is not an intermediate in any cellular activity, and has no enzymatic properties. The only function of the ligand appears to be to change the properties of the receptor.
Cell surface receptors vs Intracellular receptors
•Cell surface receptors
- Ligands are usually ___(hydrophilic) molecules that___ cross the plasma membrane
- Have ___ ligand____ domains
- Have one or more___ ____domains
- Binding of ligand causes a____ change that is communicated to the ____ domain
- Intracellular domain initiates a characteristic signal transduction pathway which can either cause a ____change in the cell or ____ changes through altering ___ and ____
•Intracellular receptors
- Ligands are ____(hydrophobic) molecules which ___ cross the plasma membrane
- Receptors are ___ ____
- Binding of ligand causes a____change that allows its ___ to ___.
- Usually induce _____ changes through changes in transcription and translation
•Cell surface receptors
- Ligands are usually polar (hydrophilic) molecules that cannot cross the plasma membrane
- Have extracellular ligand binding domains
- Have one or more membrane spanning domains
- Binding of ligand causes a conformational change that is communicated to the intracellular domain
- Intracellular domain initiates a characteristic signal transduction pathway which can either cause a rapid change in the cell or slower changes through altering transcription and translation
•Intracellular receptors
- Ligands are non-polar (hydrophobic) molecules which can cross the plasma membrane
- Receptors are transcription factors
- Binding of ligand causes a conformational change that allows its binding to DNA
- Usually induce slower changes through changes in transcription and translation
Second Messengers
•Binding of ligands to many_________ receptors activates downstream effectors which stimulate a __-lived ____ (or decrease) in the concentration of the____ ___ ____s termed second messengers
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•Either ___ or ___ from ____
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•Act as ___ ____
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•General characteristics of second messengers are
___ ____ in resting state
Regulated ___
Regulated____
Act through other ___
•Examples of second messengers are
___ ___ (____ and ___)
_____
___ ___ ( ____ and ____)
•Binding of ligands to many cell-surface receptors activates downstream effectors which stimulate a short-lived increase (or decrease) in the concentration of the intracellular signaling molecules termed second messengers
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•Either synthesized or released from storage
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•Act as intracellular ligands
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•General characteristics of second messengers are
Low amounts in resting state
Regulated synthesis
Regulated destruction
Act through other proteins
•Examples of second messengers are
Cyclic nucleotides
cAMP
cGMP
Calcium
Lipid derivatives
Inositol triphosphate (IP3)
Diacylglycerol (DAG)
G Protein-Coupled Receptors (GPCRs)
•Constitute the____ family of ___ ___ receptors
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•Despite the ___ and ___ diversity of the signal molecules that bind to them, all GPCRs have a similar ____
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•They consist of a ____ polypeptide chain that threads back and forth across the lipid bilayer ___ times and are therefore sometimes called “___ ____”, “_____” or “____” receptors
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•Receptors that bind ___ ligands have a distinct, ____ extracellular domain
•Receptors for small ligands such as ____ have ____ extracellular domains, and the ligand usually binds ___ within the plane of the membrane to a site that is formed by amino acids from ____ transmembrane segments
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•Constitute the largest family of cell-surface receptors
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•Despite the chemical and functional diversity of the signal molecules that bind to them, all GPCRs have a similar structure
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•They consist of a single polypeptide chain that threads back and forth across the lipid bilayer seven times and are therefore sometimes called “seven transmembrane”, “heptahelical” or “serpentine” receptors
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•Receptors that bind protein ligands have a distinct, large extracellular domain
•Receptors for small ligands such as adrenaline have small extracellular domains, and the ligand usually binds deep within the plane of the membrane to a site that is formed by amino acids from several transmembrane segments
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Activation of GPCRs and G proteins
•GPCRs activate _______ _____-binding proteins or _ proteins (composed of ____ protein subunits—___ ___ ___), which are anchored to the ____ leaflet of the plasma membrane
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•In the unstimulated state, the receptor and G-proteins __ or __ ___ associate; the α subunit has ____ bound and the G proteins are __
•When extracellular signaling molecules bind to GPCRs, the receptor undergoes a ____ change, which in turn alters the confirmation of the ___ proteins
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•α subunit releases its bound ___, allowing ___ to bind in its place, resulting in ____ change in α subunit. This causes the trimer to ____ from the receptor and into ___ ____components—an ___subunit and a __ complex-each then interacts with ___ downstream signaling proteins
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•GPCRs activate heterotrimeric GTP-binding proteins or G proteins (composed of three protein subunits—α, β, and γ), which are anchored to the inner leaflet of the plasma membrane
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•In the unstimulated state, the receptor and G-proteins may or may not associate; the α subunit has GDP bound and the G proteins are inactive
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•When extracellular signaling molecules bind to GPCRs, the receptor undergoes a conformational change, which in turn alters the confirmation of the G proteins
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•α subunit releases its bound GDP, allowing GTP to bind in its place, resulting in conformational change in α subunit. This causes the trimer to dissociate from the receptor and into two activated components—an α subunit and a βγ complex-each then interacts with different downstream signaling proteins
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Inactivation of G proteins
•After α subunit activates its target protein (____ protein - either ___ or ___ ____), it shuts itself ___ by hydrolyzing its bound ___ to ____
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•This ___ the α subunit, which dissociates from the t____ protein and ____s with a βγ complex to re-form an ____ G protein
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•Binding to the _____ or to___ of ___ ___ ___ (RGS) usually stimulates the GTPase activity of the α subunit
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•How does the GPCR itself get deactivated?
•After α subunit activates its target protein (effector protein - either enzymes or ion channels), it shuts itself off by hydrolyzing its bound GTP to GDP
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•This inactivates the α subunit, which dissociates from the target protein and reassociates with a βγ complex to re-form an inactive G protein
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•Binding to the target protein or to Regulators of G Protein Signaling (RGS) usually stimulates the GTPase activity of the α subunit
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•How does the GPCR itself get deactivated?
Desensitization and inactivation of GPCRs
- Ligand binds to ___
- G-proteins ____ from GPCR
- Desensitization of GPCRs begins with ____ of agonist -occupied receptors by ____ _____ (GRKs)
- ______binds to phosphorylated GPCRs, which sterically precludes coupling between the ___ and heterotrimeric ___
* *5.Receptor-bound ß-arrestins also act as ___ ____, binding to components of the ____ ____ machinery. Receptors are ____ via ___-___ ___** - ß-arrestin ____from GPCR
- Once internalized, GPCRs have two fates - ___ to the plasma membrane or ___.
- Ligand binds to GPCR
- G-proteins dissociate from GPCR
- Desensitization of GPCRs begins with phosphorylation of agonist -occupied receptors by GPCR kinases (GRKs)
- ß-arrestin binds to phosphorylated GPCRs, which sterically precludes coupling between the receptor and heterotrimeric G proteins
- Receptor-bound ß-arrestins also act as adapter proteins, binding to components of the clathrin endocytic machinery. Receptors are endocytosed via clathrin-coated pits
- ß-arrestin dissociates from GPCR
- Once internalized, GPCRs have two fates - recycled to the plasma membrane or degraded●
Depending on the ___ subunit, GPCRs can activate ___ signaling pathways
•Originally classified based on their ability to ___ (Gαs) or ___ (Gαi) the enzyme___ ___ which converts____ to ____
•Currently subdivided into _ classes – __ ___ ___ __ __ ___
•Different Gα subunits activate different ____signaling pathway
•Gβγ also can ___ signaling pathways
Gi:___ AC: ____ cAMP
Gs: ___ AC: ___cAMP
Gq: activates ___: increase ___ ___ and ___
- Originally classified based on their ability to stimulate (Gαs) or inhibit (Gαi) the enzyme Adenylate cyclase, which converts ATP to cyclic AMP (cAMP)
- Currently subdivided into 6 classes – Gαs, Gαi, Golf, G0, Gq and G11/12
- Different Gα subunits activate different effector-signaling pathway•
- Gβγ also can activate signaling pathways
Gi: inhibits AC: decrease cAMP
Gs: activates AC: increase cAMP
Gq: activates PLC: increase IP3 , DAD and cytoplasmic Ca
β1-Adrenergic Receptor Signaling
- Binding of ____ or ____ to β1-adrenergic receptor
- Activation of heterotrimeric _ proteins
- ____ of adenylate cyclase (AC) by ____
- Adenylate cyclase converts ___ to ___
* *5.Activation of ______ by ____**
Activated PKA can induce several signaling mechanisms
- phosphorylation of___ (which can either activate or inactivate those enzymes)
- Activate ___ ____ through phosphorylation
- Activate______, which in turn ____ ____ – Negative
Feedback
- Activate ___ ____– change in protein synthesis
All of the above could contribute to changes in cellular ___ ___ , ___
- Binding of norepinephrine or epinephrine to β1-adrenergic receptor
- Activation of heterotrimeric G proteins
- Activation of adenylate cyclase (AC) by Gαs
- Adenylate cyclase converts ATP to cyclic AMP (cAMP)
- Activation of protein kinase A (PKA) by cAMP
Activated PKA can induce several signaling mechanisms
- phosphorylation of enzymes (which can either activate or inactivate those enzymes)
- Activate ion channels through phosphorylation
- Activate phosphodiesterase E (PDE), which in turn degrades cAMP – Negative
Feedback
- Activate transcription factors – change in protein synthesis
All of the above could contribute to changes in cellular function, morphology, growth etc
α1-Adrenergic Receptor Signaling
- Binding of ___ or ____ to α1 adrenergic receptor causes activation of heterotrimeric _ proteins.
- Activated ___ with ___bound activates its downstream target _____
- Activated PLC hydrolyzes the membrane____ _____producing ___ and ___
- IP3 binds to and ____ a ___ ___ on ___, releasing calcium stores from inside the ER into the ____
- Calcium alters many cellular processes, in part by binding to ___ ____such as____
- The interaction of both ___and ___ with _____ activates its ____ activity and the phosphorylation of many different protein targets alters their activity.
- Binding of norepinephrine or epinephrine to α1 adrenergic receptor causes activation of heterotrimeric G proteins.
- Activated Gq with GTP bound activates its downstream target phospholipase C (PLC)
- Activated PLC hydrolyzes the membrane lipid Phosphatidylinositol 4,5-bisphosphate (PIP2), producing inositol triphosphate (IP3) and diacylglycerol (DAG).
- IP3 binds to and opens a calcium channel on ER, releasing calcium stores from inside the ER into the cytoplasm.
- Calcium alters many cellular processes, in part by binding to regulatory proteins such as calmodulin.
- The interaction of both DAG and calcium with protein kinase C (PKC) activates its kinase activity and the phosphorylation of many different protein targets alters their activity.
Receptor Tyrosine Kinases (RTKs)
•RTKs are_____proteins with their ligand-binding domain on the outer surface of the plasma membrane.
- Instead of having a cytosolic domain that associates with a trimeric G protein, however, cytosolic domain RTKs has an ____ ____ ___
- Whereas a GPCR has seven transmembrane segments, each subunit of a RTK usually has only ___ but ___ after binding ligands
•Bind ____ ligands which are ____
- ___ ___ ____ (____, ___ ____)
- ___ ____ (____)
- *-___ ___ ___ ____ ____ (___)**
•RTKs are transmembrane proteins with their ligand-binding domain on the outer surface of the plasma membrane.
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•Instead of having a cytosolic domain that associates with a trimeric G protein, however, cytosolic domain RTKs has an intrinsic enzyme activity
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•Whereas a GPCR has seven transmembrane segments, each subunit of a RTK usually has only one but dimerize after binding ligands
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•Bind diverse ligands which are proteins
-Secreted growth factors (epidermal growth factor, platelet-derived growth factor)
-Secreted hormones (insulin)
-Cell surface-bound signal proteins (ephrin)
•RTKs can be classified into 7 structural subfamilies (in mammals), each dedicated to its complementary family of protein ligands
