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BC368 Biochemistry of the Cell II. Signaling Chapter 12, pp. 433-460, 471-472 February 20, 2014. Signal transduction. Binding of acetylcholine to its receptor opens the ion channel. Signal = acetylcholine. Response= ions flow. Signal transduction. Feedback Regulation. Amplification.

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slide1

BC368

Biochemistry of the Cell II

Signaling

Chapter 12, pp. 433-460, 471-472

February 20, 2014

slide2

Signal transduction

  • Binding of acetylcholine to its receptor opens the ion channel.
  • Signal = acetylcholine
  • Response= ions flow
slide3

Signal transduction

Feedback

Regulation

Amplification

slide5

Fig. 12-1

Properties of signal transduction

slide6

Fig. 12-1

Properties of signal transduction

slide7

Fig. 12-1

Properties of signal transduction

slide8

Fig. 12-1

Properties of signal transduction

slide9

Fig. 12-1

Properties of signal transduction

  • In other words, signaling proteins can interact with more than one target, forming complexes with different properties.
slide10

Types of chemical signals

  • Cells communicate with each other by sending out signaling molecules.
  • In order to respond to the signal, target cell must have a receptor.
  • Mechanism of signal transduction depends on the chemistry of the transmitter.
slide11

Interfering with chemical signals

  • Some molecules interfere with the normal signaling pathway.
slide12

Interfering with chemical signals

  • Some molecules interfere with the normal signaling pathway.
  • Agonists bind to the receptor and mimic the effects of the normal signal.
slide13

Interfering with chemical signals

  • Some molecules interfere with the normal signaling pathway.
  • Agonists bind to the receptor and mimic the effects of the normal signal.
  • Antagonists act as competitive inhibitors of the normal signal.
slide15

Nuclear receptors

  • Nonpolar signal molecules can pass through the plasma membrane.

Steroid hormones

Thyroid

hormones

slide16

Nuclear receptors

  • Nonpolar signal molecules can pass through the plasma membrane.
  • Receptor can be in cytosol or nucleus.
  • Hormone-receptor complex acts in the nucleus to affect gene expression.
slide18

Problems with steroid signaling

  • Females who produce excess testosterone can have hyperandrogenism.

Caster Semenya

2009 World 800-Meter Champion

  • Individuals who have a defective testosterone receptor have androgen insensitivity.

Jazz singer Eden Atwood

X,Y Genotype

slide19

Anabolic Steroids

  • Anabolic steroids are testosterone agonists used to build skeletal muscle and stimulate bone growth.
  • Their use in sports was pioneered by East Germany, which had a systematic governmental doping program from 1965 to 1990.
slide20

Anabolic Steroids

  • At the first world swimming championships, in 1973, East German women won 10 of the 14 gold medals available, setting eight world records.
  • Three years later at the Montreal Summer Olympics, the East German women won 11 of 13 events.

llona Slupianek

Shot Put World Record Holder

1980 –1984

slide21

Mifepristone (RU486)

  • Progesterone signaling supports gestation.
slide22

Mifepristone (RU486)

  • Progesterone signaling supports gestation.
  • RU486 (“the abortion pill”) is a progesterone antagonist.
slide23

Thyroid Hormones

  • The thyroid normally produces T3 and T4, hormones that help in regulation of metabolism.
  • Heavy athletic training may suppress the body's production of thyroid hormones.
slide24

Thyroid Hormones

  • In 1996, endocrinologist Dr. Jeffrey Brown diagnosed sprinter Carl Lewis with exercise-induced hypothyroidism and prescribed levothyroxine (T4).
  • Brown’s patients have won 15 Olympic gold medals.
slide25

Thyroid Hormones

  • In 1996, endocrinologist Dr. Jeffrey Brown diagnosed sprinter Carl Lewis with exercise-induced hypothyroidism and prescribed levothyroxine (T4).
  • Brown’s patients have won 15 Olympic gold medals.
slide28

GS-protein pathway:

β-adrenergic receptor

slide30

G-protein activation

  • A GTP Switch protein is active when GTP is bound; inactive when GDP is bound.
slide31

G-protein activation

  • When α subunit binds GTP, it separates from β and γ.
  • Activated α subunit finds AC and turns it on.
  • Intrinsic GTPase activity turns α subunit off- it finds β and γ.
slide32

Activation of AC

  • Activated AC makes cAMP.
  • One target of cAMP is protein kinase A (PKA).
slide33

Activation of Protein Kinase A

  • PKA is active only when 4 cAMP are bound, freeing the two catalytic subunits.
  • Active PKA has many effects, depending on cell type.
slide37

Case Study

Peter T., a teacher aged 42, had just returned from Calcutta. Within 24 h of his arrival, he had suddenly developed diarrhea. It was not associated with pain, and as it was watery and voluminous, P.T. took plenty of tea to make up the body fluid. As his condition worsened, with fluid losses up to 1 L/h and with vomiting and muscle cramps, he called his doctor.

On examination, P.T. was apathetic, his cheeks were hollow, and his eyes sunken; no peripheral pulse was palpable, he was cyanotic and in a state of profound shock. He had tachycardia and his respiration was rapid and shallow. The diarrheal fluid was colorless and turbid, like “rice water.”

An isotonic solution containing Na+, K+, Cl-, and HCO3- was infused intravenously at a rate of 100 mL/min until a strong pulse was restored and thereafter in quantities sufficient to maintain normal pulse, blood pressure, and skin turgor. When the patient stopped vomiting, a solution of similar composition but containing 2% glucose was given by mouth.

Microscopic examination of the diarrheal fluid established the presence of masses of typical short, comma-shaped rods of Vibrio cholerae. A course of antibiotic therapy was started.

After 24 h the fluid loss began to decline and the patient made a rapid and complete recovery. He was estimated to have lost about 20 L of fluid containing 2.8 mol NaCl.

slide38

Box 12-2

Toxins that Target G proteins

  • Vibrio cholerae produces the cholera toxin, which ADP-ribosylates GSα, inhibiting GTPase activity.

Net result: cAMP is high

slide39

Toxins that Target G proteins

  • Bordetella pertussis produces the pertussis toxin, which ADP-ribosylates GIα, inhibiting nucleotide exchange.

GI

Pertussis

toxin

GI

Net result: cAMP is high

GI is kept off, so AC is on and cAMP levels increase

slide40

Drugs that Enhance cAMP

  • Caffeine and theophylline inhibit cAMP phosphodiesterase.

cAMP

phosphodiesterase

Net result: cAMP is high

slide41

Termination of Response

Pathway can be terminated at any step!

  • Removal of signal
  • Desensitization of receptor
  • Hydrolysis of GTP (promoted by GTPase activator proteins [GAPS])
  • Degradation of 2nd messenger
  • Hydrolysis of phosphates
slide42

Fig. 12-8

Mechanisms of Desensitization

Strategy #1: Receptor Level

slide43

Mechanisms of Desensitization

Strategy #2: Downstream Effects

  • Morphine receptor works through GI.
  • Body responds to morphine by increasing AC and PKA expression.
slide48

~Fig. 12-10

Gq acts through DAG and IP3

slide49

DAG/IP3 as Second Messengers

http://www.youtube.com/watch?v=2bbBrpgeheY

slide50

Ca2+ as Second Messenger

  • Variable Ca 2+ increases depending on the amount of IP3
slide51

Ca2+ as Second Messenger

“Because of the calcium ion’s diverse roles in cell function, it has plagued investigators from many biological disciplines for the last 30 years. Although its steady state concentration in the cytosol ranges from only 0.01 – 0.1 μM, the calcium ion triggers such diverse phenomena as lipid and glycogen degradation, the release of neurotransmitters, muscle contraction, and cell division.

How does calcium perform its varied cellular functions when it exists only in such minute quantities? It was first suggested in 1964 that the calcium ion itself is inactive; it must form a complex with one of a homologous class of calcium-binding proteins.”

-Julie T. Millard

Chemistry Honors Thesis

Amherst College, 1984

slide52

~Fig. 12-11

Ca2+ as Second Messenger

http://www.youtube.com/watch?v=07foN-1IUb4

slide55

Receptor Tyrosine kinases

  • Receptors for many growth factors, cytokines, and hormones.
  • Binding of signal initiates a kinase cascade, beginning with autophosphorylation.
slide56

Receptor Tyrosine kinases

  • Activated receptor is a dimer.

Monomer that dimerizes (e.g., epidermal growth factor receptor)

Starts out as dimer (e.g., insulin receptor)

slide57

Receptor Tyrosine kinases

  • Ligand binding causes activation of the dimer (turns on kinase activity).
  • Autophosphorylation results
slide58

Receptor Tyrosine Kinases #1: Growth Factor Receptor

  • Epidermal growth factor stimulates cell growth, proliferation, and differentiation by binding to its receptor, which is an RTK.
slide59

Receptor Tyrosine Kinases #1: Growth Factor Receptor

  • This pathway is an excellent example of signal amplication.

http://www.youtube.com/watch?v=apkY5c5DjlM

slide60

Receptor Tyrosine Kinases #1: Growth Factor Receptor

  • Epidermal growth factor stimulates cell growth, proliferation, and differentiation by binding to its receptor.
  • Signal binding to the receptor leads to a kinase cascade.

http://www.youtube.com/watch?v=OvvXgzf58MQ

slide61

Receptor Tyrosine Kinase #1: Epidermal Growth Factor Receptor

  • Ligand binding leads to receptor autophosphorylation and recruitment of adapter molecules:
  • GRB2
  • Sos
  • Binding of adapter molecules to receptor recruits and activates Ras.
slide62

Receptor Tyrosine Kinase #1: Epidermal Growth Factor Receptor

  • Activated Ras recruits Raf.
  • Binding to Ras activates Raf.
  • Raf phosphorylates MEK.
  • MEK phosphorylates MAP kinase (aka ERK).
  • MAP kinase/ERK phosphorylates its targets.
slide63

Receptor Tyrosine Kinase (RTK)/

Ras GTPase/MAP kinase (MAPK) signaling pathway

Raf

MEK

ERK

slide64

Receptor Tyrosine Kinase #1: Epidermal Growth Factor Receptor

  • Activated ERK has many substrates in the cytosol [e.g. cytoskeletal proteins, phospholipase A2, signalling proteins, and activation of transcription proteins (STATs).
  • ERK can also enter the nucleus to control gene expression by phosphorylating transcription factors such as Elk-1, growth-factor- receptor-binding protein 2, and SRF, serum response factor.
slide66

Ras: a GTP-Switch Protein

http://www.youtube.com/watch?v=TA_2WbGA0zw&list=PLAC919FD76880441F&index=43

slide67

RTK Example 2: Insulin Receptor

  • Insulin receptor is already a dimer
  • Insulin binding triggers conformational change and autophosphorylation of Tyr residues in the cytosolic region
  • Receptor then binds and phosphorylates target protein
slide68

Fig. 12-15

RTK Example 2: Insulin Receptor

  • One target is IRS-1.
  • Activated IRS-1 recruits Grb2.
  • Grb2 binds Sos.
  • Sos binds Ras.
  • Ras activates Raf-1.
  • Raf-1 phosphorylates MEK.
  • MEK phosphorylates ERK/ MAPK, which phosphorylates transcription factors.
slide69

Fig. 12-16

RTK Example 2: Insulin Receptor

slide70

RTK Example 3: EPO Receptor

  • Erythropoietin (EPO) is a peptide hormone that stimulates red blood cell production in the bone marrow.
  • An estimated 70% of professional cyclists in Europe used EPO in the mid 1990s.
slide71

RTK Example 3: EPO Receptor

  • EPO receptor has no intrinsic protein kinase activity, but recruits a tyrosine kinase (JAK).
slide72

RTK Example 3: EPO Receptor

  • EPO receptor has no intrinsic protein kinase activity, but recruits a tyrosine kinase (JAK).
  • JAK phosphorylates STAT, which dimerizes, goes to nucleus, and affects gene expression.
slide73

RTK Example 3: EPO Receptor

  • EPO receptor has no intrinsic protein kinase activity, but recruits a tyrosine kinase (JAK).
  • JAK phosphorylates STAT, which dimerizes, goes to nucleus, and affects gene expression.
  • JAK also binds Grb2, initiating the MAPK cascade.
slide75

Guanylyl Cyclases

  • When activated, these receptor enzymes convert GTP to the second messenger cGMP.
slide76

Guanylyl Cyclases

  • When activated, these receptor enzymes convert GTP to the second messenger cGMP.
  • Two types:
    • Single- transmembrane pass receptor
    • Cytosolic NO receptor
slide77

Case Study

A 56-year-old man presents to the emergency department complaining of substernal chest pain described as "something very heavy on my chest." The pain started while carrying boxes up a flight of stairs. Originally, the pain was a 9 out of 10 but after rest is now a 4 out of 10. The pain radiates to his left shoulder and is accompanied by shortness of breath. The patient states that he's had similar but less severe pain in the recent past with exertion. He wasn't going to come to the ED ("I told her it was just indigestion”), but his wife, concerned about a heart attack, made him. He has hypertension, hypercholesterolemia, and smokes a pack of cigarettes a day.

The ED nurse gives him nitroglycerine tablets, 0.4 mg sublingual (under his tongue), every 5 minutes three times. She also gives him chewable aspirin (324 mg), oxygen by nasal cannula, nitroglycerine paste on his skin, and obtains an EKG. The EKG demonstrates changes consistent with ischemia (low oxygen). Ten minutes later when the ED physician sees him, his pain is nearly gone at a 1 out of 10. Blood work, including tests for cardiac enzymes, is obtained.

The results of the blood work are normal, but due to concerns of angina the patient is admitted to the hospital. Further blood work rules out a myocardial infarction, and a stress test reveals reversible cardiac ischemia. He is diagnosed with unstable angina and is prescribed nitroglycerine to take as needed, a beta-blocker, daily aspirin, an exercise regimen, and told to stop smoking. He is scheduled for a cardiac angiogram and sent home.

slide78

Enhancing cGMP

NO

Vasodilation