Signal Transductions

Question 1

What is a signal?

Answer 1

• 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.

Question 2

Types of signalling

Answer 2

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

Question 3

Paracrine

Answer 3

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.

Question 4

Endocrine

Answer 4

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.

Question 5

Neural signaling

Answer 5

: 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.

Question 6

Autocrine

Answer 6

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.

Question 7

Two components are required for successful signalling to

occur:

Answer 7

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

Question 8

signal transduction

Answer 8

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

Question 9

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

Answer 9

1. Cell surface receptors
2. Intracellular receptors

#  Many ligands for these are steroid hormones – also thyroid 
hormone and vitamin A.

Question 10

What happens during the release of the second messenger?

Answer 10

• 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.

Question 11

Termination of signals.

Answer 11

• 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

Question 12

What happens during the first messenger stage?

Answer 12

• 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.

Question 13

The steps of cell signaling

Answer 13

1. Stimulus
   
   2. Signal
   3. Receptor
   4. Second messenger
   5. Cellular response
   6. Termination

Question 14

G-Protein coupled receptors

Answer 14

• 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

Question 15

Epinephrine signal transduction

Answer 15

• 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.

Question 16

Protein kinases in signal transduction

Answer 16

• 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.

Question 17

Points to note for cell signaling

Answer 17

+ 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.

Question 18

What is cell signaling?

Answer 18

Cell signaling is communication between and within cells.

Question 19

What are intracellular receptors? aka cytoplasmic or internal receptors

Answer 19

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

Question 20

Cell surface receptors

Answer 20

• 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.

Question 21

What is a ligand?

Answer 21

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

Question 22

Agonist

Answer 22

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.

Question 23

Antagonist

Answer 23

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.

Question 24

Three categories of cell surface receptors.

Answer 24

1. Ionotropic receptors
2. G-protein
3. Enzyme-linked protein receptors

Question 25

Ionotropic receptors

Answer 25

These are also called ligand-gated or receptor-operated ion channels = fast response in milliseconds. #ion-channel (bind ligand and open a channel through the membrane that allows specific ions to pass through)

Question 26

G-protein coupled receptors

Answer 26

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

Question 27

Enzyme-linked receptors

Answer 27

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

Question 28

Intracellular receptors

Answer 28

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

Question 29

Discuss ionotropic receptors

Answer 29

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+.

Question 30

How does specificity occur?

Answer 30

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.

Question 31

Discuss G-protein coupled receptors

Answer 31

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

Question 32

G-protein coupled receptor and signal transduction

Answer 32

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

Question 33

-Receptors can be inactivated in at least three OTHER ways

Answer 33

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.

Question 34

Cessation of Activity in Signal | Transduction Pathways

Answer 34

* 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.

Question 35

Discuss intracellular receptors

Answer 35

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

Question 36

An enzyme-linked receptor-the leptin receptor

Answer 36

. 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.

Question 37

Discuss enzyme-linked receptors

Answer 37

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

Question 38

Amplification of signals in signal transduction.

Answer 38

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

Question 39

Protein Kinases in signal transduction

Answer 39

• 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

Question 40

Phospholipase C

Answer 40

• 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

Question 41

Second messenger systems

Answer 41

• 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

Question 42

Adenylate cyclase and cAMP

Answer 42

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.

Question 43

G-protein family

Answer 43

``` Gs - Adenylate cyclase Gi - Adenylate cyclase Gq - Phospholipase C Go - Phospholipase C Gt - Phosphodiesterase ```

Question 44

G-protein family and affected enzymes

Answer 44

``` Gs - Adenylate cyclase Gi - Adenylate cyclase Gq - Phospholipase C Go - Phospholipase C Gt - Phosphodiesterase ```

Question 45

Gs - Adenylate cyclase

Answer 45

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

Question 46

Gq - Phospholipase C

Answer 46

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