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Biochemistry > Yokomori 2 > Flashcards

Yokomori 2 Flashcards

1
Q

What are some properties of G protein-coupled receptors? What is it used for?

A

-superfamily of seven-pass transmembrane receptor proteins (N is outside, C is inside cytosol)
-located in plasma membrane
-signals transmitted by conformational change,GTP binding, and hydrolysis of G protein complex in cytosol
-diverse ligands (unlike nuclear receptors which use hydrophobic hormones)
-40% of prescription drugs target GPCRs
fxn:
1) organismal homeostasis
2) embryonic and gonadal development
3) learning and memory

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2
Q

WHat is epinephrine (adrenaline) and what does it do?

A
  • important in response to stress, such as fright or heavy exercise
  • in liver and adipose cells: liberates glucose and FA by glycogenolysis and lipoylysis
  • in heart muscle cells: increase contraction rate, increases blood supply to tissue
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3
Q

What are examples of antagonists/agonists for epinephrine? What are agonist and antagonist?

A
  • drugs such as METAPROLOL (beta blockers) are B1-adrenergic receptor selective antagonists, which slow heart contractions in treatment of cardiac arrhythmia and angina
  • B2-receptors agonist such as ALBUTEROL for asthma, can relax smooth muscle opening bronchioles
  • agonist and antagonist are synthetic analogs of natural hormones which bind to receptor and induce normal response (agonist) or do not induce downstream response (antagonist); latter is an inhibitor
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4
Q

Describe G protein activation

A

1) GDP bound to alpha subunit is inactive
2) binding of subunit causes conformational change which causes the G protein complex to bind, which also changes conformation; releasing GDP and picks up GTP through nonspecific interactions (GTP concentration much higher inside cell than GDP)
3) This causes change in alpha subunit, releases G protein complex and beta-gamma subunits from alpha subunit
4) Alpha with GTP binds to effector protein, activating it
5) Hydrolysis of GTP to GDP causes alpha to dissociated from effector and reassociate with beta-gamma

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5
Q

What are the different mechanisms of enzyme activation by G proteins?

A

1) Beta-gamma can also activate enzyme
2) beta-gamma and alpha can activate diff enzymes (dual regulation)
3) Conditional regulation (beta gamma needs alpha for activation of enzyme)

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6
Q

What % of GPCR are expressed in the brain?

A

90%; GPCR is very important in brain activity

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7
Q

What are 3 types of G proteins?

A

1) G(s-alpha) : effector is adenylyl cyclase, 2nd messenger: cAMP (increased); ie. epinephrine receptor, receptors for glucagon
2) G(i-alpha): effector is adenylyl cyclase and K+ channel, 2nd messenger: cAMP (decreased) + changes in membrane potential; ie. alpha1-adrenergic receptor, acetylcholine receptor
3) G(q-alpha): effector is phospholipase C, 2nd messenger: IP3 and DAG (increased); alpha2-adrenergic receptor

only need to know effector and 2nd messengers

DONT MEMORIZE

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8
Q

Describe how acetycholine-induced K+ channel affects heart muscle contraction.

A

Binding of acetylcholine causes beta-gamma to activate opening of K+ channel, causes K+ to leave cell resulting in REDUCED frequency of heart muscle contraction

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9
Q

What are the two major G protein signaling cascades?

A

Gs -> adenylyl cyclase -> cAMP
Gq -> phospholipase C-beta -> IP3 -> Ca2+ -> PKC
or IP3 -> DAG -> PKC

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10
Q

How do Gs and Gi compete?

A
  • Gs (epinephrine, glucagon, ACTH) activates adenylyl cyclase when activated
  • Gi (PGE1, adenosine) inhibits adenylyl cyclase when activated
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11
Q

How does cholera toxin work?

A
  • Inactivates Gs-alpha
  • cholera toxin acts as ADP-ribosylation and prevents inactivation of G protein by inhibiting hydrolysis of GTP
  • causes massive diarrhea and dehydration from excess water flow from blood into lumen of intestine
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12
Q

How does pertussis toxin work?

A
  • causes whooping cough (vomiting and dehydration)
  • prevents release of GDP from Gi-alpha so complex cannot be inhibited; hyperactivation of adenylyl cyclase due to lack of inhibitory activity
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13
Q

How does cAMP-dependent protein kinase (cAPK or PKA) work?

A

1) PKA normally inactive (regulatory and catalytic subunits); 2 regulatory, 2 catalytic subunits
2) binding of cAMP to regulatory subunits (2 on each subunit) release them and catalytic units are then active

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14
Q

What is the overall activation of Gs pathway?

A

Gs -> adenylyl cyclase -> cAMP -> PKA (serine-threonine kinase) -> phosphorylation of different pathways

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15
Q

How does PKA activate transcription factor CREB?

A

CREB: cAMP responsive element binding protein

  • PKA phosphorylates CREB allowing it to interact with coactivator (associated with HAT activity) and activates gene transcription
  • important for brain genes for memory
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16
Q

Glucagon and epinephrine stimulate glycogen _______. How?

A

stimulate glycogen breakdown

1) glucogon bound to glucagon receptor in liver to activate cAMP production
2) epenipherine bound to B-adrenergic receptor in muscle and liver activate cAMP production

17
Q

How do cortisol, epinephrine + norepinephrine, and glucogon regulate glycogenolysis and gluconeogenesis?

A

cortisol: 0, ++
epinephrine + norepinephrine: +++, 0
glucagon: +, +

18
Q

How does cAMP impact glycogen metabolism in liver and muscle cells?

A

increased cAMP:

1) stimulates glycogen breakdown by phosphorylation
2) inhibition of glycogen synthesis by phosphorylation

decreased cAMP:

1) inhibition of glycogen breakdown by dephoshorylation
2) stimulation of glycogen synthesis by dephosphorylation

Liver increases glucose level by as much as 50%

19
Q

What are the types of diabetes?

A

1) type 1; genetic autoimmune disease destroying insulin secreting cells
2) type 2; most common. insulin resistance caused by obesity

20
Q

Describe inositol phospholipid (IP3/DAG) pathway in Gq protein.

A

1) activation of phospholipase C cleaves PIP2 (PI 4,5-bisphosphate) into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3)

DAG for activating PKC
IP3 for activating Ca2+ release

21
Q

Describe how Ca2+ is released and the consequences. And what about DAG?

A

After activating phospholipase C, IP3 is released which binds to IP3-gate Ca2+ channel in ER membrane. Stimulates release of Ca2+ into the cytosol

DAG is also released with IP3 to activate PKC which is activated with binding of Ca2+. This goes on to phosphorylate other substrates.

22
Q

What else does Gq activation do?

A

Hydrolysis of PIP2 causes release of Tubby which is now active and enters the nucleus where it regulates eating behavior. Mutation in tubby = obesity

23
Q

Why is Ca2+ signaling efficient? What are the ways it can be done?

A
  • Normally very low intracellular Ca2+ so rapid influx is useful in signaling
    1) nerve terminal - depolarization stimulates opening of Ca2+ gate
    2) Gq pathway
24
Q

What is the structure of calmodulin, what is it activated by?

A

Binds 4 Ca2+, causes conformational change that binds to target proteins and change their conformation, altering activity

25
Q

What is an example of calmodulin activity?

A
  • Ca/calmodulin-dependent protein kinase II (CaM kinase II) activation
    1) active calmodulin binds and exposes active site for autophosporylation
    2) fully active CaM kinase can keep acting (50-80% when no Ca2+) until it is deactivated by dephosphorylation
26
Q

What is the overall pathway of Ca released by Gq?

A

Gq -> phospholipase C-beta -> IP3 -> Ca2+ -> calmodulin -> CaMK II or calcineurin

27
Q

How is contractility of arterial smooth muscle by nitric oxide (NO) and cGMP regulated?

A

1) acetycholine binds to GPCR which stimulates phospholipase C -> IP3 -> calmodulin -> NO synthase
2) NO synthase produces NO from arginine + O2
3) NO acts as signaling molecule for smooth muscle cells (has short half life)
4) NO receptor produces cGMP -> PKG -> relaxation of muscle cell

28
Q

What is cardiac hypertrophy?

A

adaptive response of heart to cardiac disease, including that arising from HT, mechanical load, MI, mutations in cardiac contractile protein genes, etc.
-responses of cardiomyocytes include increase in cell size and up-regulation of fetal cardiac genes.

29
Q

What is hypertrophic cardiomyopathy (HCM)?

A

sustained hypertrophy that can lead to dilated cardiomyopathy, heart failure, and sudden death

1) hypertrophy if left ventricle and is often asymmetric
2) myocellular disarray and increased fibrosis
3) dilated cardiomyopathy (resulting in cell death)

30
Q

What is familial hypertrophic cardiomyopathy (FHC)?

A

1/500
leading cause of sudden cardiac death in young athletes due to mutations in sarcomeres; “sarcomeric disease”
-related to Ca2+ release which triggers hypertrophic response of cardiomyocytes

31
Q

What is calcineurin?

A
  • serine/threonine phosphatase
  • activated by sustained Ca2+ and Ca2+/calmodulin; insensitive to Ca2+ fluxes
  • expressed in immune cells (T cells)
  • target for inhibition by cyclosporin A (CsA) and FK506
  • can cause hypertrophy
32
Q

What else does calcineurin target?

A
  • hypertrophy by dephosphorylation of NFAT
  • is a nucleofactor activator of T cells (where it is discovered)
  • NFAT 3 in heart
  • inhibitors of calcineurin can reverse cardiac hypertrophy (ie CsA and FK506); can’t be used in humans due to conflict with T cells
  • dephosphorylation activates NFAT
33
Q

How is GPCR desensitized?

A

1) when GTP binds to G-alpha, affinity of the receptor for hormone ligand decreases leading to dissociation of hormone from receptor
2) heterologous desensitization by the second-messenger-regulated kinases and other kinases such as PKA, PKC, leads to decreased activation of adenylyl cyclase. they phosphorylate the receptor
3) activated receptors activate GPCR kinases (GRKs) resulting in activation-dependent regulation of receptors of homologous desensitization; also inteferes with G-alpha’s binding to effectors
4) Receptor phosporylation induces Beta-arrestin recruitment leading to receptor endocytosis

homologous vs heterologous desensitization
phosphatases are required for “reset”

34
Q

How does beta-arrestin work?

A

Phosphorylation of GPCR activates beta-arrestin

1) triggers endocytosis
2) activates MAP kinase cascade
3) activates c-Jun kinase cascade

Biochemistry (12 decks)

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