Biochem Chapter 11

Front 1

What are types of chemical messengers?

Back 1

*Hormones

*Neurotransmitters

*Cytokines

*Retinoids

*Growth Factors

*some bind to surface receptors

*some have second messenger transmittance

Front 2

What messengers bind to intracellular receptors?

Back 2

Nuclear hormone

Front 3

What receptors have messengers bind to the surface of the receptors?

Back 3

*Ion channels

*Tyrosine kinase receptors

*G protein-Coupled receptors

Front 4

What are second messenger transmitting signal?

Back 4

1. Secretion of chemical message

2. Binding of message to cell surface receptor

3. Diffusion of a hydrophobic message across plasma membrane and binding to an intracellular receptor

Front 5

What are some nervous system chemical messengers?

Back 5

*Small molecule neurotransmitters (biogenic amines)

*Neuropeptides (4-35 AA)

Front 6

What are some endocrine system chemical messengers?

Back 6

• Polypeptidehormones (insulin)

• Steroidhormones

• Thyroidhormone

• Retinoids(aka retinol)

Front 7

What are some chemical messengers of the immune system?

Back 7

• Cytokinesare small proteins

• Chemokines (induce movement towards source of chemokines)

Front 8

What are ecicosanoids and their functions?

Back 8

• Eicosanoids – prostaglandins (Eicosanoids are derived from arachidonic acid andretain its original 20 carbons – all prostaglandins, such as prostacyclin (PGI2)contain an internal ring)

• Short-termsignaling molecules

• Respondto injuries

• PGI2vasodilation

Front 9

What are some examples of growth factors?

Back 9

*they are polypeptides

• PDGF (Platelet-derived)

• EGF (epidermal)

Front 10

What are the 3 models of cell-cell signaling?

Back 10

Endocrine, paracrine and autocrine actions ofhormones and other chemical messengers

Front 11

What is the endocrine cell-cell signaling pathway?

Back 11

*Has distant targets

*Messengers are estrogen hormones

*Messengers travel in the blood and are secreted into the blood

Front 12

What is the paracrine cell-cell signaling pathway?

Back 12

*Has local targets

*Messengers are neurotransmitters

*an example is acetylcholine

*Messengers travel between nearby cells

Front 13

What is the autocrine cell-cell signaling pathway?

Back 13

*Self signaling

*Chemical messengers are T cells and cancer cells

*Act on the same cell that produces the message

Front 14

What are plasma membrane receptors?

Back 14

*Cell-surface receptors

*Plasma membrane receptors are bound by polar molecules

-messengers: peptide hormones, cytokines, and catecholamines

-Have extracellular binding domains

Front 15

What are intracellular receptors?

Back 15

*Bound by hydrophobic molecules

-messengers: steroid hormones, thyroid hormone, retinoic acid

-can bind other messengers that are able to pass through the plasma membrane

*Receptors may reside in the cytoplasm and translocate to the nucleus, in the nucleus bound to DNA, or in the nucleus bound to other proteins

Front 16

What are the steroid hormone-thyroid hormone superfamily?

Back 16

- Nuclear hormone receptors: RAR, TR, VDR, AR

· RAR: Retinoid acid receptor (9-cis-retinoicacid)

· TR: Testicular receptor

· VDR: Vitamin D receptor-like

· AR: Androgen receptor

- Heterodimers with RXR (9-cis-retinoid acidreceptor) bind DNA, activate transcription

- Mineralcorticoid (aldosterone) andglucocorticoid (cortisol) receptors

Front 17

What are ion-channel receptors and some examples?

Back 17

– They bind small-molecule neurotransmitters, neuropeptides

*Acetylcholine (ACh) receptors at theneuromuscular junction

· Nicotinic ACh receptor

Front 18

What is the signaling pathway of the nicotinic ACh receptor?

Back 18

Ø High specificity

Ø Nerve signal

Ø Ach vesicles released

Ø Bind Ach receptors on muscle

Ø Open iron channel

Ø Triggers muscle contraction

Front 19

What is the structure of the nicotinic ACh receptor?

Back 19

· Composedof 5 subunits each subunit has 4-membrane spanning helical regions

· When twoAch molecules are bound, the subunits change their conformation so that thechannel in the center of the receptor is open, allowing K+ ions to diffuse outand Na+ ions to diffuse in

Front 20

What are kinase receptors?

Back 20

– The intracellular domain of the receptor (a kinase)is activated when the messenger binds to the extracellular domain (Ligandbinding activation).

– The receptorkinase phosphorylates an amino acid residue on the receptor or associatedprotein.

Front 21

What is protein kinase?

Back 21

o Protein kinases transfer a phosphate group (PO43-)from ATP to the –OH group of a specific amino acid side chain (S, T, or Y)in the target protein

Front 22

What are some examples of kinase receptors?

Back 22

*Tyrosine Kinase Receptor

*JAK-STAT receptor (just another kinase) and (signal tranduces and activator of transcription)

*Serine-threonine kinase receptor

* All have kinase domain intracellularly

Front 23

What are heptahelical receptors?

Back 23

– Most common

– Contain 7 membrane-spanning αhelix

– Work through 2nd messengers (small molecules such as cAMP,DAG, IP3)

Front 24

What are some examples of Heptahelical receptors?

Back 24

*Heterotrimeric G proteins

*Adenylyl cyclase and cAMP phosphodiesterasePhosphatidylinositide signaling by heptahelicalreceptors

Front 25

What are the chemical messengers of the serpentine receptors and what are the second messengers produced?

Back 25

*Hormone, ctyokine, or neurotransmitter

*cAMP, diacylglycerol (DAG), or insitol triphosphate (IP3)

Front 26

What is the RAS and the MAP kinase pathway?

Back 26

· Monomer with single membrane-spanning helix

· Dimerization once bound by growth factor· Autophosphorylation

· Binding of Grb2 and SOS

· SOS binds Ras, enabling binding of GDP to Ras

· ActivatedRas binds Raf, activating MAP pathway

· MAP pathway terminate at a gene transcription factor

Front 27

What is the signal transduction by tyrosine kinase receptors?

Back 27

1.Binding and dimerization.

2. Autophosphorylation.

3. Binding of Grb2 and SOS.

4. SOS is a GEF (guanine nucleotide exchange factor) that binds Ras, amonomeric G protein anchored to the plasma membrane.

5. GEF activates theexchange of guanosine triphosphate (GTP) for bound guanosine diphosphate (GDP)on Ras.

6. Activated Ras containing GTP binds the target enzyme Raf, therebyactivating it and a series of downstream kinases known as themicrotubule-associated protein (MAP) kinase pathway.

Front 28

What is Grb2?

Back 28

oneof the proteins with an SH2 domain that binds to phosphotyrosine residues ongrowth factor receptors. Binding to the receptor causes a conformational changein Grb2 that activates another binding site called an SH3 domain. Theseactivated SH3 domains bind the protein SOS (SOS is an acronym for"son of sevenless," a name that is not related to the function orstructure of the compound).

Front 29

What is phosphatidylinositol?

Back 29

· Phosphatidylinositol4’,5’-biphosphate (PI-4,5-bisP) can be cleaved to generate the two intracellular second messengers DAG & IP3

Front 30

What is Phosphatidylinositol 3’,4’,5’-triphosphate?

Back 30

· (PI-3,4,5,-trisP) can serve as a plasma membranedocking site for signal transduction proteins(GIP anchor picture)

* Major route for generation of thephosphatidylinositide signal molecules

Ø Phosphotidulinositide (PI) signaling moleculescan be generated through either tyrosine kinase receptors or heptahelicalreceptors

Front 31

What are the insulin receptor signaling paths?

Back 31

- Binding ofhormone causes autophosphorylation

- Binds IRS(insulin receptor substances), PO43- those:

· Grb2 can signal through Ras and MAPK path

· Other proteins bind, interact with PIPs in membrane

Front 32

What is the signal transduction by JAK-STAT receptors?

Back 32

- Associated withtyrosine kinase JAK

- Used by cytokinesto regulate cell proliferation of immune response

- STATsare gene specific transcription factors

Front 33

What is the function of the Serine-Threonine kinase?

Back 33

- Used by transforminggrowth factor superfamily

- Smad proteinsregulates transcription of specific genes

· Meaning theyactivate or inhibit transcription

- The Smad dimer either activates or inhibits the expression of target genes

Front 34

What are GPCRs?

Back 34

G Protein-Coupled Receptors (GPCRs) representsignal-transducting molecules that transmit signals to cells

Front 35

What are the functions of GPRCs?

Back 35

- They play a key role in converting extracellularstimuli into intracellular responses, and are therefore responsible for allphysiological processes

- Dysfunctional GPCRs are the prime cause for ahost of human diseases, both physiological and pathophysiological, ranging fromallergies, depression to hypertension

Front 36

What are some drugs that bind GPCRs?

Back 36

- Eli Lilly’s Zyprexa, Schering-Plough’s Clarinex,GlaxoSmithKline’s Zantac, and Novartis Zelnorm

Front 37

What is the structure of GPCRs?

Back 37

- Have 7-helix membrane-spanning domains- Coupled to trimeric G proteinsG proteins composed of α, β and γ chains: Gs,Gi, Gq, Gt

Front 38

What are the secondary messengers of GPCRs?

Back 38

- Activate a chain of cellular events eitherthrough adenylate cyclase (AC) pathway or the phospholipase C (PLC) pathway

· 2nd messenger: cAMP, IP3 and DAG

- Activated G binds to GTP

- Inactivated G binds to GDP

Front 39

What is the function of the alpha s subunit?

Back 39

Stimulates adenylyl cyclase

Front 40

What is the function of the alpha i/o subunit?

Back 40

Inhibits adenylyl cyclase

Front 41

What is the function of the alpha t subunit?

Back 41

Stimulates cGMP phosphodiesterase

Front 42

What is the function of the alpha q subunit?

Back 42

Activates phospholipase Cbeta

Front 43

What is the function of the alpha 12/13 subunit?

Back 43

Activate Rho-GEF (guanine nucleotide exchange factor)

Front 44

What is the cAMP pathway?

Back 44

- Hormone binds receptor

- Trimeric G protein in membrane is engaged- Adenylate cyclase is stimulated

- cAMP level is changed

- Protein kinase A is activated

- Protein phosphorylation and gene expression

Front 45

What does intracellular signaling?

Back 45

- Lipophilic hormones

· Steroid hormones

· Thyroxine and retinoic acid

Front 46

What are some ways that a signal can be terminated?

Back 46

*Diffusion degradation

*Protein phosphatases

*GTPases

*Phosphdiesterases

•Some turn off quickly, othersslowly

•Many different steps

•Diseases from persistence ofsignal:

–Cancerand Ras

Front 47

What is myasthenia graivs

Back 47

• Autoimmune disease

– Antibodiesdirected against nicotinic ACh receptor in skeletal muscle.

• Fatigue and inability to do repeated tasks• Numbers of ACh receptors greatly reduced• Inhibitor of acetylchoinesterase brieflyincreases muscle strength

Front 48

What is anorexia nervosa?

Back 48

• Endocrine hormones mobilize fuels from adiposetissue

• Epinephrine (adrenaline) (GPCR) promotes fuelmobilization

• Different receptors on different cells (ex.Glucagon receptors on liver, not on muscle; liver does gluconeogenesis)

• Insulin (special RTK=Receptor tyrosine kinases) promotesfuel storage

Front 49

What is cholera?

Back 49

– Choleratoxin activates adenylate cyclase• ActivatesGs by ADP-ribosylation (Therefore, the enzyme remains continually activated)

Front 50

What is pertusis?

Back 50

– Pertusistoxin activates adenylate cyclase• InactivatesGi by ADP-ribosylation (Therefore, Gi cannot perform its normal function toinhibit adenylate cyclase. Then, conversion of ATP to cyclic AMP cannot bestopped.) (gene continues to be produced)

Front 51

What is graves' disease?

Back 51

– IgGauto-Abs stimulate TSH receptors

– TypeII hypersentivity

Front 52

What is mutant RAS protein?

Back 52

– Verylow GTPase activity but permanently active

– Increasedcell proliferation

Front 53

What are some agonist (stimulatory effects) drugs?

Back 53

• Ephedrine:α1, vasoconstriction

• Albuteroland terbutaline: α2,bronchodilator

Front 54

What are some antagonists (inhibitory effects) drugs?

Back 54

• β-blockers: nonselective(propranolol, timolol); β1selective (metoprolol, atenolol)

• Losartan:blocks angiotensin II receptors• Antipsychotics:chlorpromazine, haloperidol, block D2 receptors

Front 55

What must happen for protein kinase B to become active?

Back 55

The inactive form is not phosphorylated but must be phosphorylated to become active.