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Mechanisms of Disease > Lecture 3 > Flashcards

Lecture 3 Flashcards

1
Q

4 General Types of Signaling

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2
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4 General Types of Signaling

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  1. Direct Cell-Cell Signaling

Immune system, Integrins and cadherins

  1. Endocrine Signaling

The signal goes everywhere but only certain cells have receptors that can sense the signal. (hormones)​

3.  **Paracrine Signaling**

Eicosanoids, neurotransmitters

 4.  **Autocrine Signaling**

Immune system, Cancer

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3
Q

Direct Cell-Cell Signaling

A

•Immune cells such as B cells, T cells, macrophages.

–Highly mobile

–Express signaling molecules on their cell surface

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4
Q

Endocrine Signaling

A

•Specificity occurs at the receptor level.

–Cells without receptors ignore the signal.

–The signal is distributed throughout the body.

–Provides a perfect way to coordinate distant body parts towards one function.

  • Regulation occurs both at the point of release and at the point of signal detection.
  • Widely used by many different tissues for many different purposes.

–Examples include steroid hormones, insulin, and adrenaline

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5
Q

Paracrine signaling

A

•A method to keep a signal more or less localized.

–Regulation occurs at the level of generating the signal.

–If the molecule is unstable it will only diffuse a few cell diameters before much of it is degraded.

•Widely used by many different tissues for many different purposes.

–Example: Nitric oxide (NO) is secreted by vascular endothelial cells and acts on vascular smooth muscle to promote relaxation.

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6
Q

Synaptic transmission is a specialized form of Paracrine Signaling

A
  • The synapse is a specialized structure in which only a very small amount of fluid separates the presynaptic cell from the post synaptic cell.
  • The concentration of the neurotransmitter is quite high with little or no leakage.
  • Diffusion from presynaptic terminal to postsynaptic receptor is extremely rapid.
  • Allows neighboring cells to carry completely different signaling information.
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7
Q

Synaptic transmission is a specialized form of Paracrine Signaling

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8
Q

Autocrine Signaling

A
  • Provides a positive feedback loop.
  • Useful for rapidly promoting proliferation.
  • The immune response arises from the activation of a single T cell
  • Cancer cells make use of this process to rapidly divide as well.
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9
Q

Insulin Release

A
  • Blood sugar levels are sensed by the beta cell of the islets of Langerhans within the pancreas.
  • Pre-proinsulin is converted to insulin in vesicles derived from the Golgi.
  • When glucose levels rise, it induces a transient release of Ca++. This promotes the fusion of the vesicles with the surface of the beta cell and the release of their contents.
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10
Q

Insulin Slide

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11
Q

Histamine Release

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  • Histamine is released from Mast cells in response to allergens.
  • Allergens bind to IgE expressed on the surface of the Mast cell.
  • Binding induces a signal transduction cascade that mobilizes Ca++ which promotes vesicular fusion.
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12
Q

Histamine Slide

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13
Q

Cleavage from the membrane

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•Tumor necrosis factor (TNFα) is an important inflammatory signaling protein

–TACE is a protease that cleaves TNFα. Note that this is NOT a quantal release mechanism.

–Soluble TNF now can diffuse to its site of action.

•Both membrane bound TNFα and soluble TNFα can activate TNFα receptors on neighboring cells.

–Blockade of TNF signaling is an important therapy for treating rheumatoid arthritis.

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14
Q

Cleavage from the membrane slide

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15
Q

Continuous Release

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•Some signaling molecules are released as soon as they are made.

–Steroid hormones (estrogen, progesterone, testosterone, corticosterone, aldosterone, etc.)

–Prostaglandins

–Many cytokines (other than TNFα)

•In this case regulation is at the level of synthesis of the signaling molecule.

–The release is NOT quantal in character.

–Regulation could be transcriptional (synthesis of mRNA) or translational (synthesis of protein).

  • Peptides are released via a continuous vesicular exocytosis
  • Small (uncharged) molecules diffuse out of the cell
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16
Q

Transport- Diffusion

A
  • Diffusion allows all cells within an area to receive the signal. If we couple this with the signal being unstable and thus short lived we have a good mechanism to keep the signal localized.
  • Keeping the signal local is a strategy for maintaining specificity.
  • Local signaling allows one molecule to be used for many different physiological purposes.
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17
Q

Diffusion- Prostaglandins

A

•Prostaglandins are an excellent example of signaling molecules that provide local signaling. Many of them spontaneously degrade within minutes and others are actively degraded by enzymes in the lung.

–Prostaglandins are heavily used during inflammation.

–Prostaglandins are also used by several organs to regulate blood flow including the heart and the kidney.

–Prostaglandins are used in the brain to regulate fever.

–(this is not an inclusive list – prostaglandins are involved in a vast number of processes).

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18
Q

Gradient mediated developmental processes

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19
Q

Gradients also create a direction

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20
Q

Receptor

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A specific protein in either the plasma membrane or interior of a target cell with which a chemical messenger combines to exert its effects.

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21
Q

Down-regulation

A

A decrease in the total number of target cell receptors for a given messenger in response to chronic high extracellular concentration of the messenger.

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22
Q

Up-regulation

A

An increase in the total number of target cell receptors for a given messenger in response to chronic low extracellular concentration of the messenger.

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23
Q

Ligand

A

A compound (small molecule or protein) which binds to a receptor. A ligand can be an endogenous compound or a drug.

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24
Q

Affinity

A

The strength with which a chemical messenger binds to its receptor.

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25
Q

Agonist

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A chemical messenger that binds to a receptor and triggers the cell’s response; often refers to a drug that mimics an endogenous messenger’s action.

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26
Q

Antagonist

A

A molecule that competes for a receptor with an endogenous chemical messenger. The antagonist binds to the receptor but does not trigger the cell’s response.

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27
Q

Saturation

A

The degree to which receptors are occupied by a messenger. If all are occupied, the receptors are fully saturated; if half are occupied, saturation is 50%; etc.

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28
Q

Specificity

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Selectivity; the ability of a receptor to react with a limited number of structurally related types of molecules.

29
Q

Competition

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The ability of different molecules very similar in structure to combine with the same receptor.

30
Q

Receptor Binding versus Cellular Effect

A
  • The effect of a signal on a cell is not binary. The number of receptors activated can correlate with the strength of the cellular effect.
  • A maximal signal can often be elicited when only a small fraction of receptors are activated. This is referred to as the spare receptor theory.
  • Receptor signal strength can be modulated.

–With many important receptor systems, the cell has the ability to either increase the signal strength or decrease the signal strength caused by the occupancy and activation of a receptor.

•Loss of receptor sensitivity is known as desensitization. Increased receptor sensitivity is called priming.

31
Q

**Intracellular Receptors-Steroid Hormone **

A
32
Q

**Ion Channels: **

Acetylcholine Receptor

A
  • The acetylcholine receptor (ACh) cycles between 3 states: resting, open, and desensitized.
  • The binding of ACh drives the receptor into the open state.
  • Continued binding of ACh, however, drives the receptor into the desensitized state which is closed.
  • Removal of ACh allows the receptor to reassume the resting state.

–ACh is degraded by cholinesterases.

33
Q

**Ion Channels: **

Acetylcholine Receptor

Slide

A
34
Q

Ion Channels and the Glucose Sensor

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35
Q

Sulfonylurea drugs

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36
Q

Gap junctions

A
  • Gap junctions span a gap between adjacent cells and couples the cytoplasm of both cells.
  • A channel is created by 6 connexin molecules forming a hexagonal structure.
  • Two channels have to line up from two neighboring cells for a functional connection to be made. Only when these two channels connect is a gap junction formed.
37
Q

Gap Junctions

A

•Gap junctions open and close. This process is regulated:

–Low intracellular calcium (Cai++) opens the channel

–High Cai++ closes the channel

–Thus Ca__++__ is the ligand and the gap junction is the receptor.

–The purpose of closing the gap junction is to protect the cell. A sustained increase in Cai++ is indicative of cellular damage.

38
Q

Gap Junction mediated communication

A

•The gap junction pore is small. Only ions and metabolites may pass through.

•How is this used by the body?

–Electrical coupling: Tissues such as the heart and smooth muscle are able to react very quickly to changes in electrical stimulation by contracting due to movement of ions though the gap junction.

–Metabolic signaling: The liver produces glucose from amino acids when needed (gluconeogenesis). Adrenaline/epinephrine is secreted from nerve terminals to signal this event. As not all liver cells are next to nerve terminals, the signal is propagated through the gap junction rapidly increasing the liver’s response to maintain glucose homeostasis.

39
Q

Gap Junction Inhibition

A
  • New research has generated data suggesting that intracellular inflammatory signaling molecules may also spread quickly through a tissue via gap junctions in the liver.
  • Drug induced liver injury is a major issue and is one of the most common reasons why the development of a new drug may be abandoned.
  • Acetaminophen (Tylenol®) is a model compound in this regard.

–Acetaminophen dosage is limited in people for this reason.

–High acetaminophen doses can reproducibly cause liver injury in animal models.

•Patel and colleagues have recently shown a direct connection between gap junctions and drug induced liver injury.

–Mice genetically engineered to be missing a liver gap junction gene are resistant to liver injury.

–They identified a small molecule inhibitor of liver gap junctions and then showed that it protects against acetaminophen induced liver injury.

40
Q

All G Protein Coupled Receptor Have 7 Transmembrane Domains

A
  • There are many different G protein coupled receptors and all have retained this 7 transmembrane structure.
  • A ligand will make hydrogen bonds with the amino acids found on the outside of the cell.

–The number and strength of hydrogen bonds determines the affinity of the ligand for its receptor.

–The position of the hydrogen bonding amino acids determines the specificity of the receptor: only some ligands can interact.

  • Binding causes the relatively stiff alpha helices to slide and rotate against each other.
  • This has a very large effect on the conformation of the intracellular side of the receptor.
41
Q

All G Protein Coupled Receptor Have 7 Transmembrane Domains

A
42
Q

G Proteins Migrate Along the Membrane to Their Target

A
  • Activation of this class of receptor results in the activation of an associated protein known as a G protein. It is so called because it binds GTP.
  • The G protein is associated with the receptor when inactive.
  • Upon activation the G protein releases from the receptor and migrates along the membrane to interact with its target.
  • The target is usually an enzyme, which, depending on the G protein will either be turned on or turned off.
43
Q

G Proteins Migrate Along the Membrane to Their Target

A
44
Q

Tyrosine Kinase

Linked Receptors:

Activation via dimerization of subunits

A

•Each subunit contains a kinase activity, however as a monomer, the kinase has no access to substrate.

–The substrate for each kinase is the other subunit.

–By dimerizing, the two subunits supply each other with their substrates.

•Phosphorylation alters the charge and thus, the conformation of the intracellular surface creating a new binding site which recruits further signaling components

45
Q

**Tyrosine Kinase **

Linked Receptors:

Activation via dimerization of subunits- Slide

A
46
Q

The ß adrenergic receptor

A
47
Q

Physiological functions of the ß adrenergic receptor

A
  • Increase heart rate
  • Increase blood pressure
  • Decrease airway resistance
  • Increase gluconeogenesis
  • Increase muscle glycogen breakdown
  • Fight or flight response
48
Q

Heath issues addressed by manipulating this pathway

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•Heart disease

–Blocking b adrenergic receptors will decrease blood pressure.

•Asthma

–Activating b adrenergic receptors will open the airway (decrease airway resistance)

49
Q

G proteins hydrolyze

GTP to GDP

A
50
Q

cAMP Levels are Dynamically Regulated

A
51
Q

cAMP binds to the regulatory subunits of PKA

A
52
Q

**PKA phosphorylates numerous cellular proteins at serine and threonine residues **

A
53
Q

Signal Amplification is an Important Component of Signal Transduction

A
54
Q

G-proteins Couple Receptors to Many Different Signaling Systems

A
55
Q

The Muscarinic Acetylcholine Receptor Family

A
56
Q

The Muscarinic Acetylcholine Receptor Family

A

M1, M4 and M5 receptors: CNS. These receptors are involved in complex CNS responses such as memory, arousal, attention and analgesia. M1 receptors are also found at gastric parietal cells and autonomic ganglia.

M2 receptors: heart. Activation of M2 receptors lowers conduction velocity at sinoatrial and atrioventricular nodes, thus lowering heart rate.

M3 receptors: smooth muscle. Activation of M3 receptors at the smooth muscle level produces responses on a variety of organs that include: bronchial tissue, bladder, exocrine glands, among others.

57
Q

Physiological Function of the Muscarinic Acetylcholine Receptor

A

•The “feed or breed” response.

–Decreased heart rate and blood pressure

–Increased blood flow to gut.

–Decreased muscle glycogen breakdown and gluconeogenesis.

•Health issues addressed by this pathway are somewhat more specialized than we observed with the b adrenergic system.

58
Q

Muscarinic receptors decrease blood pressure via nitric oxide (NO)

A
59
Q

Calcium Signaling

A
  • Calcium has the unique property of being both an electrical and a chemical signaling entity.
  • Processes that are regulated by calcium binding include:

–Muscle contraction (actin:myosin interactions)

–Cytoskeletal movement.

–Vesicular fusion with the membrane.

–Modulation of kinase activity.

•Many of the chemical signaling events mediated by calcium occur through interactions with specific proteins.

–The most important calcium binding protein, however, is calmodulin.

–Underlying its importance, calmodulin makes up 1% of ALL protein in the cell.

60
Q

Calmodulin

A
61
Q

CaM kinase II

A
62
Q

Receptor Tyrosine Kinases:

Example: the EGF receptor

A
63
Q

Ras

A

•Ras functions very much like a G protein however it has a different structure and does not bind to serpentine receptors and thus is classified separately.

–There are actually quite a lot of different Ras-like proteins. We refer to them as the Ras monomeric GTPase superfamily.

–All members of the family are tethered to the membrane with a covalently attached lipid group (__farnesyl group).

•Ras does a number of things. In addition to insulin signaling it is involved in the process of proliferation.

–Blockade of Ras blocks cell proliferation in vitro while activation of Ras promotes proliferation.

–Importantly, 30% of human cancers have activating ras mutations.

•Ras has recently been targeted in the form of inhibiting the transfer of the lipid (farnesyl group) onto the protein.

–This class of drug is called farnesyl transferase inhibitors.

–Ras is still functional but it no longer localizes to the membrane.

64
Q

The MAPK signaling cascade

A
65
Q

Complexity in MAP kinase cascade signaling

A
66
Q

The MAPK machine

A
  • While we do not know exactly why things evolved this way, the 3 kinase cascade is very useful.
  • There exist several different MAPKKKs, MAPKKs, and MAPK proteins. Many of these can interact to form different cascades and exist within the same cell.

–Thus a dozen or so proteins can form literally hundreds of different and unique cascades.

–Specificity is maintained by preassembling these units.

–Several proteins have been found which seem to function as scaffolds for these 3 kinase units. This constitutes one possible way in which these machines are constructed.

  • Thus by having a 3 kinase cascade one can combine different inputs and outputs using an adaptor (middle) kinase.
  • Within the same cell, receptor tyrosine kinase #1 can activate one MAPK cascade while receptor tyrosine kinase #2 can activate a different cascade with differing effects while using shared MAPK components.
67
Q

The duration of the signal can have profound consequences

A
  • Using the MAP-kinase cascade as an example:
  • Epidermal Growth Factor (EGF) mediated Ras activation peaks at 5 minutes and then declines.

–Some hours later, the cell divides.

•In contrast, Nerve Growth Factor (NGF) mediated Ras activation remains high for hours.

–The cell leaves the cell cycle and differentiates.

68
Q

Summary

A
  • Signals can be local (affecting only 1 or a few neighboring cells) or global affecting many tissues simultaneously.
  • The signal is transmitted to the target cell via a receptor which changes conformation when the signal binds.
  • The signal is transmitted via a cascade of events involving both covalent and conformational changes.

–Phosphorylation is a major strategy and can function as either an on switch or an off switch depending on the protein and where it is phsophorylated.

–Formation of protein complexes can promote conformational changes that activate proteins.

•Signaling complexes are sequestered within the cell providing a measure of specificity and context.

Mechanisms of Disease (6 decks)

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