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Title: Study Guide


1
Study Guide
  • How do hormones regulate adenylyl cyclase
    activity? PLC activity?
  • Describe the mechanism of regulation of PKA by
    cAMP
  • Contrast diabetes mellitus type I and type II
  • Describe the architecture of insulin and the
    insulin receptor
  • How does insulin activate the Raf-MEK-ERK
    pathway?
  • How does glucagon produce hyperglycemia?
  • How does one treat diabetic hypoglycemia?

2
How Do Hormones Regulate cAMP levels and PLC
Activity?
  • Seven transmembrane segment receptors that
    interact with G-proteins
  • G-protein GTPase activity
  • Gs stimulates adenylyl cyclase
  • Gi inhibits adenylyl cyclase
  • Gq activates phospholipase C (PLC)
  • Leads to generation of two messengers
  • Diacylglycerol, activates PKC
  • Inositol 1,4,5 trisphosphate, releases Ca2 from
    intracellular stores in the ER

3
G-Protein Cycle (Fig. 19-10)
4
Regulation of Adenylyl Cyclase (Fig. 19-11)
Gs activates adenylyl cyclase (12) Gi inhibits
adenylyl cyclase
5
Cyclic AMP Metabolism Revisited (Fig. 10-13)
6
How Does Glucagon Lead to an Acute Rise in Blood
Glucose?
  • Earl W. Sutherland, Jr. asked how does
    epinephrine injection in dog lead to
    hyperglycemia?
  • Epinephrine in dogs uses the beta adrenergic
    receptor and the cAMP second messenger system
    (Sutherlands system)
  • Epinephrine in rats, mice, and humans works via
    the alpha receptor and not by the cAMP protein
    kinase A cascade
  • In liver, glucagon activates its receptor, Gs,
    and adenylyl cyclase to increase cAMP and
    activate PKA glucagon in humans works the same
    as epinephrine in the dog
  • This leads to a cascade that activates glycogen
    phosphorylase
  • This leads to the inhibition of glycogen synthase
  • Review Daniel Stewarts presentation on 11
    February 2004

7
The Protein Kinase Reaction
  • ATP protein ? phosphoprotein ADP
  • PKA is a serine/threonine kinase
  • It is a broad specificity enzyme with many
    substrates

8
Fig 10-8 Overview of Glycogen Metabolism
9
Regulation of Glycogen Metabolism (Fig. 10-14)
cAMP activates PKA this illustrates the actions
of PKA
10
Phospholipase C and Inositol (Fig. 19-13)
11
Diabetes Mellitus
  • A relative or absolute deficiency of insulin
  • Chronic hyperglycemia and disturbances of
    carbohydrate, lipid, and protein metabolism
  • Incidence
  • 16 Million Americans aged 20 years and older and
    the incidence is increasing
  • 60-70 patients per thousand dental patients 50
    are not diagnosed
  • Increases with obesity
  • Polydipsia, polyphagia, polyuria is the classic
    triad understand the mechanisms
  • Hyperglycemia leads to polyuria as glucose
    transport maximum is exceeded
  • Polyuria leads to polydipsia
  • Loss of energy (calories) leads to excessive food
    intake, or polyphagia
  • Type I insulin-dependent, juvenile, immunologic
    destruction of the beta cells of the islets of
    Langerhans 10
  • Type II Adult onset 90

12
Comparison of Type I and II Diabetes Mellitus
13
Metabolic Disorders Associated with Type II
Diabetes
  • Hyperglycemia
  • Dyslipidemia
  • Elevated triglycerides
  • Decreased HDL (Good Cholesterol)

14
Diabetes Mellitus Complications
  • Retinopathy
  • Vision changes
  • Most common cause of blindness in the US
  • Nephropathy (renal failure)
  • Neuropathy
  • Sensory, loss of sensation in hands, feet, legs
  • Autonomic
  • Change in cardiac rate, rhythm, conduction
  • Impotence
  • Accelerated cardiovascular disease and
    atherosclerosis
  • Peripheral vascular disease (amputations)
  • Coronary artery disease
  • Stroke
  • Hypertension
  • Dental complications
  • Alterations in wound healing
  • Increased incidence of infections
  • Xerostomia
  • Increased incidence of oral candidiasis
    (controversial)

15
Diabetes and Periodontal Health
  • Risk factor for prevalence and severity of
    gingivitis and periodontitis
  • Altered host defense secondary to diabetes may
    contribute
  • Increased collagen breakdown owing to increased
    collagenase production
  • Not only does diabetes promote periodontal
    disease, but periodontal disease can make the
    diabetes more difficult to control (any
    inflammatory flare up can increase insulin
    requirement)
  • Possible findings in an undiagnosed diabetic
  • Severe, progressive periodontitis
  • Enlarged gingiva that bleed easily when
    manipulated
  • Multiple periodontal abscesses

16
Abscesses in Diabetes
17
Periodontitis in Diabetes
18
What do I do with a patient suspected of having
diabetes?
  • Ask whether the patient has experienced
    polydipsia, polyphagia, polyuria
  • Probably will be negative, but you have to ask
  • This classical triad is associated with type I
    diabetes more often than type II diabetes
  • Symptoms for type II diabetes include lethargy
    and fatigue
  • Recent weight loss (paradoxical in an obese
    person)
  • Family history, i.e., a parent or sibling with
    diabetes
  • Refer to your sister-in-law, the internist
  • Diagnosis
  • Fasting blood glucose
  • Normal lt 110 mg/dL diabetes gt 126 mg/dL
  • 2-hour serum glucose after 75 g of glucose PO
  • lt140 mg/dL diabetes gt 200 mg/dL
  • Hemoglobin A1c
  • Normal lt6 diabetes gt7 (usually 10-15)
  • Glucosuria this was noted by Dr. Thomas Willis
    (of the circle of Willis)
  • The urine of the diabetic patient.the spirits of
    honey

19
Formation of Hb A1c (Fig. 7-5)
20
Insulin
  • 51 residues
  • Two chains
  • 3 Disulfide bonds
  • What happens when you remove Asn21?
  • Produced in which cells of the pancreas?
  • Hyperglycemia ? increased secretion
  • First protein to be sequenced Fred Sanger

21
Insulin Receptor Protein-Tyrosine Kinase
  • Insulin stimulates glucose uptake in muscle and
    fat, glycogen synthesis, lipogenesis, and protein
    synthesis, and insulin inhibits lipolysis,
    proteolysis, and glycogenolysis
  • Insulin receptor undergoes autophosphorylation
    and phosphorylates IRS1-4 (Insulin receptor
    substrates 1-4), PI3 kinase binding protein, and
    Shc
  • Expressed in almost all cells, but at much higher
    levels in liver, fat, and muscle
  • Insulin does not increase glucose transport into
    the liver

22
Protein-Tyrosine Kinase (PTK) Cascades
  • Initial step represents the activation of a PTK
  • The enzyme is not active as a monomer it must
    dimerize
  • There is transphosphorylation A phosphorylates
    A, and A phosphorylates A to achieve activation
  • These phosphotyrosines can function as docking
    sites
  • Attraction of proteins to the docking sites can
    be regulatory
  • The PTK may phosphorylate other proteins that can
    serve as docking sites, or they may activate or
    inhibit activity

23
Insulin Receptor
  • It is a protein-tyrosine kinase
  • It autophosphorylates itself and insulin
    substrates
  • The resulting phosphotyrosines serve as docking
    proteins that attract Grb2 and Shc
  • These attract Sos, a GEF, and Ras to start the
    signal transduction cascade

24
Insulin Receptor Architecture
  • Insulin binds to the N-terminal half of the
    a-subunit
  • Human autoantibodies recognize 450-601
  • Y965, Y972 yields sites for PTB (phosphotyrosine
    binding) domains that are found in IRS1-4 and Shc
  • After IRS binds to pY972, it can be
    phosphorylated
  • pY1334 binds SH2 domains of p85 regulatory
    subunit of PI3 kinase

25
Ras GTP-Cycle (Fig. 20-3)
  • Ras is a GTPase
  • It is on one pathway for insulin action
  • It is on many other pathways that lead to cell
    growth and division
  • Ras is frequently mutated in cancer (25 of all
    human cancers)

26
Grb2, Sos, and Ras
  • pY of IRS binds SH2 of Grb2
  • SH3 of Grb2 binds to Sos (son of sevenless, a
    GEF)
  • Sos mediates the exchange

27
Ras-Raf-MEK-ERK Overview
  • Raf-Mek-ERK is associated with cell growth and
    cell division
  • MEK is a dual specificity kinase
  • However, it can lead to apoptosis
  • The final result depends upon the conditions, or
    context
  • It is not clearly understood
  • SOS GEF

28
Docking Sites and Activation
29
Insulin Receptor and PI3 Kinase
30
The PI-3 Kinase Pathway
  • Activated allosterically by binding to
    protein-tyrosine phosphate
  • Catalyzes the phosphorylation of PIP2 to form
    PIP3
  • PIP3 activates phosphoinositide-dependent protein
    kinase (PDK) allosterically
  • PDK phosphorylates S6K, PKB (AKT), and PKC
  • PKB phosphorylates glycogen synthase kinase 3
    (GSK3)

31
PI3 Kinase Cascade and Insulin
32
Phosphoprotein Phosphatase-1
  • Insulin stimulates glycogenesis in muscle, but
    epinephrine stimulates glycogenolysis
  • Glycogenolyis (breakdown) is associated with
    phosphorylation (the cascade)
  • Glycogenesis (build up) is associated with
    dephosphorylation
  • Insulin promotes the dephosphorylation of
    glycogen synthase and phosphorylase
  • These reactions are catalyzed by the catalytic
    subunit of PPase-1
  • Insulin leads to the phosphorylation and
    activation of PPase-1
  • Epinephrine leads to the phosphorylation and
    inactivation of PPase-1

33
Phosphoprotein Phosphatase-1 (Fig. 20-5)
34
Diabetes the Glucagon/Insulin Ratio
  • Glucagon
  • Produced by the alpha cells of the islets of
    Langerhans
  • Early preparations of insulin produced
    hyperglycemia followed by hypoglycemia
  • The hyperglycemic factor represented
    contamination
  • This factor was purified, characterized, and
    re-named glucagon
  • It produces hyperglycemia by at least three
    mechanisms
  • It promotes glycogen breakdown as noted above
  • It inhibits glycolysis and increases
    gluconeogenesis
  • cAMP activates PKA, which phosphorylates
    fructose-6-phosphate-2-kinase/fructose-2,6-bisphos
    phatase
  • This decreases fructose-2,6-bisphosphate
  • This removes a stimulant of glycolysis at the PFK
    step
  • This removes an inhibitor of gluconeogenesis at
    the fructose-1,6-bisphosphatase step
  • PKA promotes transcription of PEP carboxykinase,
    an important enzyme in gluconeogenesis
  • The high ratio of glucagon/insulin action
    promotes hyperglycemia

35
Regulation of Fructose 2,6-BP
Fig 7-11
  • Glucagon increases cAMP and PKA activity
  • PKA increases Frc 2,6 BPase activity and
    decreases Frc 2,6 BP
  • Glycolysis decreased, gluconeogenesis increased

36
Reciprocal Regulation of Glycolysis and
Gluconeogenesis (Fig. 25-2)
37
Insulin Action
  • Stimulates glucose transport into muscle, adipose
    tissue, and many other cells EXCEPT liver
  • This results from the recruitment of GLUT4 (of
    GLUT1-GLUT7)
  • Glucose transporters contains 12 transmembrane
    segments
  • Mechanism of recruitment is unclear
  • It does not rely on new transporter synthesis
  • GLUT4 associated with internal membranes fuses
    with the plasma membrane
  • Insulin promotes glycogen synthesis by inducing
    the production of glycogen synthase

38
Glucose Transporter with 12 TM Segments
39
GLUT Recyling
40
Diabetic Hypoglycemia
  • One of the five most common dental emergencies
  • Usually due to inadequate food intake
  • Ask every person receiving insulin whether they
    have eaten prior to Rx
  • If the answer is no, provide food before
    providing Rx
  • Characterized by confusion, agitation, anxiety,
    hostility (the previous four can be described as
    acting weird), dizziness, tachycardia,
    sweating, tremor
  • Severe loss of consciousness
  • Make presumptive Dx of hypoglycemia
  • Rx
  • If conscious, give 15 g oral carbohydrate 4-6 oz
    fruit juice or soda hard candy usually respond
    in a few minutes
  • If unable to take food by mouth, give 50 glucose
    IV (LSUHSC SOD)
  • If unable to take food by mouth, give 1 mg
    glucagon sq or im (This is not standard practice
    here.)

41
Angiotensin System
  • Renin, a proteolytic enzyme, is released from the
    juxtaglomerular (JG) cells of the kidney and
    converts angiotensinogen to angiotensin I
  • Angiotensin converting enzyme (ACE) catalyses the
    conversion of angiotensin I to angiotensin II
  • Angiotensin II is a potent vasoconstrictor and
    promotes the formation of aldosterone (increases
    Na reabsorption)

42
Angiotensin Metabolism
43
ACE Inhibitors
  • These compounds decrease peripheral
    vasoconstriction and decrease aldosterone
    synthesis
  • This class of drugs are widely used in the Rx of
    hypertension

44
Lipophilic First Messengers
45
Lipophilic Hormones
  • These hormones can diffuse through plasma and
    nuclear membranes
  • The intracellular receptors , which constitute
    the nuclear-receptor superfamily, function as
    transcription activators when bound to ligand
  • Receptor architecture
  • C-terminal variable segment
  • Middle DNA binding region with a C4 zinc finger
    segment
  • N-terminal hormone (ligand) binding domain
  • In some receptors, this domain functions as a
    repression domain in the absence of ligand

46
Lipophilic Hormones
  • The DNA binding sites, or response elements have
    been determined
  • Inverted repeats bind symmetric receptor
    homodimers GRE, ERE
  • These are found in the cytoplasm in the absence
    of ligand bound to Hsp90 (heat shock protein of
    MW 90 kDa)
  • Binding of hormone releases the Hsp and allows
    nuclear translocation
  • After translocation and binding to its HRE, it
    activates transcription by interacting with
    chromatin-remodeling and histone acetylase
    complexes
  • Direct repeats bind with heterodimers with a
    common receptor called RXR VDRE, TRE, RARE
  • The vitamin D3 response element is bound by the
    RXR-VDR heterodimer
  • Heterodimers are located exclusively in the
    nucleus
  • These repress transcription in the absence of
    ligand
  • They direct histone deacetylation at nearby
    nucleosomes
  • In the liganded state they direct
    hyperacetylation

47
Steroid Receptor Superfamily
48
Steroid Hormone Action
49
Hormone Response Elements (HREs)
50
The End
  • Biochemistry is fun!!!
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