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F) Vino Lectures - Term 1 > Signal Transductions > Flashcards

Signal Transductions Flashcards

Beyond the cell as well

1
Q

What is a signal?

A
  • Signals are messages sent to different parts of the body to them function more efficiently.
  • Many types: Epinephrine. released during acutely stressful conditions from adrenal glands. It is a primary messenger- released into blood.
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2
Q

Types of signalling

A
  1. Paracrine
  2. Endocrine
  3. Neural signaling
  4. Autocrine
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3
Q

Paracrine

A

this is where molecules called local hormones are released into
the local environment of the cell producing the signal. These act on cells in the immediate environment.

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4
Q

Endocrine

A

the signal is called a hormone and is released into the blood
where it can circulate to the whole body. However, it will only affect cells
and tissues that have receptors for the hormone.

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5
Q

Neural signaling

A

: this is a particular type of signaling that can be both paracrine and autocrine. A signal generated in a nerve cell travels along nerve fibers to the effector. These signals travel electrically down these fibers until the target is reached, where a chemical called a neurotransmitter is released locally. This signal can act either on the releasing nerve cell (autocrine), or on the nearby target (paracrine), which may be an effector, such as a muscle or gland, or another nerve.

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6
Q

Autocrine

A

these molecules act on the cell releasing the signal. This is the mode of action of
many growth hormones. Unregulated release of growth hormones can lead to the formation
of tumours.

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7
Q

Two components are required for successful signalling to

occur:

A

-You need a signaling molecule
–You need a receptor molecule that recognizes the signal and acts
upon it

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8
Q

signal transduction

A

The signaling molecule (ligand) binds to the receptor at a
specific binding site and produces an effect in the target cell
(the effector)

-Signal transduction at the cellular level refers to the
movement of signals from outside the cell to inside
• Or transforming a signal from one form to another

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9
Q

Receptors are specific in their binding and mediate specific
responses what are the two main categories of receptors?

A
  1. Cell surface receptors
  2. Intracellular receptors
#  Many ligands for these are steroid hormones – also thyroid 
hormone and vitamin A.
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10
Q

What happens during the release of the second messenger?

A
  • The second messenger = the change of shape of the membrane protein causes activity within the cell, like activation of some protein or enzyme. The message has now been Transduced into the cell. Now there’ll be an increase in the production of intracellular molecules called Second messengers, e.g. cAMP, cGMP, and Ca2+, the second messengers amplify the original signal.
  • Second messengers diffuse around the cell and interact with different compartments of the cell. Effectors respond to second messengers and then carry out cellular processes that lead to a physiological response.
  • Second messengers can induce transcription, enzymes, activate pumps, and channels.
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11
Q

Termination of signals.

A
  • When a cell receives a signal, it performs certain function or many functions in response to the stimulus. This cannot go on forever, so there must be a way to terminate the signal and the second message and so on. If the body fails to terminate the signal then there will be severe consequences to cell and organism.
  • Summary- RECAP
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12
Q

What happens during the first messenger stage?

A
  • Primary messenger needs to attach onto a receptor that is specific to it.
  • Receptors are on cell membranes, and they are transmembrane proteins- have intracellular and extracellular component.
  • Ligand binds to extracellular component of receptor [=receptor-ligand-complex] causing a change in structure of the membrane protein.
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13
Q

The steps of cell signaling

A
  1. Stimulus
    1. Signal
    2. Receptor
    3. Second messenger
    4. Cellular response
    5. Termination
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14
Q

G-Protein coupled receptors

A
  • signal receptors, extracellular domain (part), then it passes transmembrane seven times. its a seven transmembrane helix receptor. it has 7 alpha helices that cross the membrane 7 times [7TM]. Called Serpentine [looks like a snake]
  • Many different primary messengers bind to the extracellular domain of G-protein coupled receptors. primary messengers like Hormones, neurotransmitters and drugs.
  • 7TM receptors also have internal binding domain. - hetero trimeric
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15
Q

Epinephrine signal transduction

A
  • Epinephrine binds to a[ G- protein-coupled receptor] 7TM receptor CALLED Beta-adrenergic receptor. It has a domain on the inside that attaches a heterotrimeric protein with alpha, beta and gamma domains. The alpha - is a g-protein because ithas the ability to bond guanyl nucleotides.
  • When nothing is bound to the receptor the g-protein binds GDP, and the 3 subunits remain attached to each other and can associate with the 7TM.
  • When Epi binds , conformational change occurs in the 7TM and the g-protein loses affinity for GDP and binds GTP. Beta and gamma dissociate from the alpha.
  • As long as the Epi is bound and the 7TM is activated many g-proteins exchange GDP —> GTP amplifying internal change.
  • The disassociated alpha domain [with GTP] binds to adenylyl cyclase [a transmembrane protein]. The adenylyl cyclase converts ATP to cAMP . cAMP is second messenger , many ATP –> many cAMP.
  • cAMP stimulates activity of protein kinase A, activate other enzymes.
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16
Q

Protein kinases in signal transduction

A
  • Have central role
  • control cell function: Enzymes, transport proteins, muscle contraction, cell division and differentiation, cytokine synthesis, ion transport via ion channels, energy metabolism.
  • Second messengers are available but not always active.
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17
Q

Points to note for cell signaling

A

+ Different drugs stimulate or inhibit production of second messenger.
+ cAMP made from ATP via membrane bound adenylate cyclase enzyme.
+ The cAMP activates cAMP dependant protein kinase- aka Protein kinase A [PKA]
+ The PKA regulates variety of cell functions incl.: Cell division, Muscle contraction, ion transport, energy metabolism.

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18
Q

What is cell signaling?

A

Cell signaling is communication between and within cells.

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19
Q

What are intracellular receptors? aka cytoplasmic or internal receptors

A

located in the cytoplasm of the cell and are activated by hydrophobic ligand molecules that can pass through the plasma membrane.

20
Q

Cell surface receptors

A
  • proteins that are present in or on cells , there for binding specific ligands, which activate many cellular processes.
  • Cell-surface receptors bind to an external ligand molecule and convert an extracellular signal into an intracellular signal.
21
Q

What is a ligand?

A

Ligand called a receptor agonist when it binds to
specific receptor, activates it and produces a cellular
response
• When it binds and produces no effect, but prevents
binding of another agonist, it is called an antagonist
• Binding is usually rapidly reversible depending on
presence of ligand
• Interaction between ligand and receptor weak –
hydrogen, ionic bonds and van der Waals forces
• Covalent bonds are prolonged and may be irreversible
–new receptors need to be synthesized if required

22
Q

Agonist

A

An agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response. In contrast, an antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite to that of the agonist.

23
Q

Antagonist

A

A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of receptor proteins.

24
Q

Three categories of cell surface receptors.

A
  1. Ionotropic receptors
  2. G-protein
  3. Enzyme-linked protein receptors
25
Q

Ionotropic receptors

A

ion-channel (bind ligand and open a channel through the membrane that allows specific ions to pass through)

These are also called ligand-gated or receptor-operated ion channels = fast response in milliseconds.

26
Q

G-protein coupled receptors

A

(bind ligand and activate a membrane protein called a G-protein, which interacts with either an ion channel or an enzyme in the membrane

metabotropic receptors or 7 TM spanning
receptors – membrane receptors coupled to
intracellular effector systems via a G-protein
(named due to interaction with GDP and GTP –
the response is 100ms to seconds)

27
Q

Enzyme-linked receptors

A

enzyme linked-protein receptors(are cell surface receptors with intracellular domains that are associated with an enzyme.)

Enzyme linked receptors or kinase linked
receptors are membrane receptors that
incorporate an intracellular protein kinase domain
within their structure – tissue response occurs in
minutes.

28
Q

Intracellular receptors

A

or DNA linked
nuclear receptors regulate gene transcription and
located in cytoplasm or nucleus – response time
in hours to days

29
Q

Discuss ionotropic receptors

A

Usually targets for fast neurotransmitters
• Nicotinic receptors – 5 subunits around a
central pore –stimulated by acetylcholine
• Gamma-amino-butyric acid A (GABAA
-R)
similar to nicotinic receptor - selective for
anions esp Cl-
• Glutamate – excitatory amino acid
neurotransmitter found in CNS – two
classes of glutamate receptors
– NMDA (N-methyl-D-aspartate) and non
NMDA receptors
– Ligand-gated channels that are voltage-gated
– For ions to flow the receptor must bind
glutamate and be depolarized
– Allows for a significant influx of Ca2+.

30
Q

How does specificity occur?

A
  1. specific ligand will have specific receptor that binds only that ligand.
  2. not all cells have receptors for each ligand, so that only cells that have the receptor are capable of detecting and responding to the signal.
31
Q

Discuss G-protein coupled receptors

A

A large family of transmembrane proteins
• Metabotropic because they initiate a chain of events
inside cell known as a second messenger system
• It is a single polypeptide chain with an N-terminal
extracellular domain, 7 transmembranes (TM) domains
• TM5 and TM6 loop contains a binding site for G
proteins where second messengers are produced

32
Q

G-protein coupled receptor and signal transduction

A

A major player in signal transduction is the G-protein
• G protein is a heterotrimer consisting of three
different subunits α, β, and γ
• 3 subunits attached to the cell membrane by fatty
acid chain
• Bound to the intracellular surface but free to move
around so can interact with a variety of enzyme

When a ligand binds to GPCR, enzyme action causes a
change in the αβγ trimer
• The trimer dissociates into α and βγ subunits
• The α and βγ subunits are the active forms of G
protein that diffuse in the plane of the membrane
• They interact with various enzymes and ion channels
• Initiate production of second messengers

33
Q

-Receptors can be inactivated in at least three OTHER ways

A
  1. The receptor becomes chemically altered (usually by
    phosphorylation), which may lower its affinity for a first
    messenger, and so the messenger is released.
  2. Phosphorylation of the receptor may prevent further G protein
    binding to the receptor.
  3. Plasma membrane receptors may be removed when the
    combination of first messenger and receptor is taken into the
    cell by endocytosis.
34
Q

Cessation of Activity in Signal

Transduction Pathways

A
  • Once initiated, signal transduction pathways are eventually shut off because chronic overstimulation of a cell can in some cases be detrimental.
  • The key event is usually the cessation of receptor activation. Responses to messengers are transient events that persist only briefly and subside when the receptor is no longer bound to the ligand.
  • A major way that receptor activation ceases is by a decrease in the concentration of first messenger molecules in the region of the receptor.
  • This occurs as enzymes in the vicinity metabolize the first messenger, as the first messenger is taken up by adjacent cells, or as it simply diffuses away.
35
Q

Discuss intracellular receptors

A

Intracellular and nuclear receptors found in cytoplasm and
nucleus
• Act on DNA to alter genetic expression of enzymes, cytokines
and receptor proteins
• Therefore initiates different patterns of protein synthesis to
give different effects
• Ligands are all lipid soluble and diffuse through cell
membrane
• Inactive form binds to heat shock proteins
• Travels through nuclear pore when bound to hormone and
interacts with hormone response elements (zinc fingers) on
DNA
• Binding activates genes but can inhibit as well
• Steroid hormones inhibit or induce specific genes by binding
to specific DNA due to receptor having a DNA binding
domain

36
Q

An enzyme-linked receptor-the leptin receptor

A

. The receptor exists as a homodimer (two identical parts),
and leptin binds to the extracellular part of the receptor, causing phosphorylation and activation of the intracellular associated Janus kinase 2 (JAK2). This causes phosphorylation of signal transducer and activator of transcription (STAT) proteins, which then activates the transcription of target genes and the synthesis of proteins. JAK2 phosphorylation also activates several other enzyme systems that mediate some of the more rapid effects of leptin.

37
Q

Discuss enzyme-linked receptors

A

Kinase receptors
• Hormone receptors and transmembrane proteins
• Extracellular ligand domain and intracellular catalytic
a domain that has enzyme activity when activated
• Extracellular domain very large to accommodate large
hormones such as insulin
• Enzyme site is a protein kinase: tyrosine kinase and
guanylate kinase
• Promotes cell growth and differentiation
• Eg insulin, platelet-derived growth factor, cytokines,
leptin
• Focus on kinase receptor research for treatment of
cancers, immune disorders, inflammation

38
Q

Amplification of signals in signal transduction.

A

When ligand bound to the receptor as much as 20 Gprotein subunits will be activated
• G proteins will activate effector enzyme eg adenylate
cyclase
• Each effector enzyme will produce a number of seconds
messenger molecules
• Each messenger molecule will active second enzyme
systems eg PKA
• This activates further molecules that activate
numerous reactions within the cell
• Cascades
• Single ligand causes a cascade of activity within the cell

39
Q

Protein Kinases in signal transduction

A

• Have a central role in signal transduction
• Control cell function:
– Enzymes, transport proteins
– Muscle contraction – increase rate and force of cardiac
muscle, increase gut motility and secretion
– Energy metabolism via neurotransmitter release
– Ion transport via action on ion channels esp Calcium
– Cell division and differentiation
– Cytokine synthesis

40
Q

Phospholipase C

A

• Phospholipase C (PLC) is a membrane-bound enzyme, which
when activated by a G-protein, converts membrane
phospholipid phosphatidylinositol 1,4-bisphosphate (PIP2
) to
inositol 1,4,5-triphosphate (IP3
) and diacylglycerol (DAG)
• Inositolphosphates controls intracellular calcium
– It diffuses into the cytoplasm and binds to receptors on ER to
release intracellular Ca2+
– It also causes the influx of Ca2+ ions
• DAG remains membrane-bound and activates protein kinase
C (PKC) which:
– catalyzes the phosphorylation of proteins
– is involved in the transduction of a wide variety of processes
including inflammation, ion transport, modulation of
neurotransmitter release and smooth muscle contraction
– Raised intracellular Ca2+ concentration also activates PKCs

41
Q

Second messenger systems

A

• GPCRs control various cellular effector systems via
the G-protein – two pathways
• Cyclic nucleotide system:
– Adenylate cyclase synthesizes cyclic adenosine
monophosphate (cAMP) from ATP
– Guanylate cyclase synthesizes cyclic guanosine
monophosphate (cGMP)
– Phospholipase C catalyzes the formation of inositol
triphosphate (IP3
) and diacylglycerol (DAG)
• Also targets ion channels

42
Q

Adenylate cyclase and cAMP

A

Different drugs stimulate or inhibit production of second messenger
• cAMP synthesized from ATP via membrane bound adenylate cyclase
enzyme
• cAMP activates cAMP dependent protein kinase –also known as Protein
Kinase A (PKA)
• PKA regulates variety of cell functions including:
– Cell division
– Muscle contraction
– Ion transport
– Energy metabolism
• cGMP works in a similar fashion to cAMP.

43
Q

G-protein family

A 
Gs - Adenylate cyclase
Gi - Adenylate cyclase
Gq - Phospholipase C 
Go - Phospholipase C 
Gt - Phosphodiesterase
44
Q

G-protein family and affected enzymes

A 
Gs - Adenylate cyclase
Gi - Adenylate cyclase
Gq - Phospholipase C 
Go - Phospholipase C 
Gt - Phosphodiesterase
45
Q

Gs - Adenylate cyclase

A

Increased cAMP = Opens Ca2+ channels and closes Na+ channels

46
Q

Gq - Phospholipase C

A

IP3, DAG = IP3 releases intracellular calcium from stores and closes calcium channels

F) Vino Lectures - Term 1 (11 decks)

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