Updated: 4/9/2020

Signal Transduction

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Tyrosine kinase signalling
  • Tyrosine kinase structure
    • dimeric transmembrane protein
    • intrinsic kinase activity
    • phosphorylated receptor can bind protein called insulin receptor substrate (IRS)
      • is a scaffold protein
  • Pathway
    • hormone binds to receptor
    • receptor is dimerized
    • auto cross-phosphorylation of intracellular domain of the dimerized receptor
    • IRS binds phosphorylated domian
    • IRS is phosphorylated on SH2-domains
    • several enzymes bind phosphorylated SH2-domians
      • phosphatases
        • pathway signaled for by insulin
      • kinases
        • phosphoinositol-3 (PI-3) kinase
      • G proteins
        • ras
          • oncogene present in many cancer
          • constitutive activation leads to constant growth signal
  • Examples
    • insulin, PDGF, EGF receptors
    • sensitization via PPAR-gamma 
G protein signalling
  • G-protein structure
    • trimeric enzyme
      • α, β, γ
        • α-subunit has intrinsic GTPase activity
          • acts as timer for shutting off the active form
  • Pathway
    • hormone binds to receptor:G-protein complex on cell membrane
    • GDP bound to inactive α-subunit is exchanged for GTP
    • α-subunit now active
      • can be inhibitory (Gi) or stimulatory (Gs, Gq)
    • is released from β, γ subunits
    • can act as 2 different effector mechanisms
      • cAMP pathway
        • Gs activates adenyl cyclase
          • normally, ATP → cAMP to increase [cAMP]
          • cAMP can activate protein kinase A
          • Cholera and E. coli toxins
            • ADP-ribosylates subunit of Gs, which activates G
            • ↑↑↑ [cAMP]
        • Gi inhibits adenyl cyclase
          • normally, stops ATP → cAMP to decreases [cAMP]
          • Pertussis toxin
            • ADP-ribosylates subunit of Gi, which inhibits Gi
            • ↑↑↑ [cAMP]
      • PIP2 pathway
        • Gq activates phospholipase C
          • PIP2 → IP3 + DAG
            • DAG can activate protein kinase C
            • IP3 can release Ca2+ from the ER
              • Ca2+ then activates a number of enzymes including protein kinase C
    • GTP eventually hydrolyzed to GDP and α-subunit becomes inactive
  • Examples
    • cAMP = glucagon, epinephrine (β, α2)
    • PIP2 = vasopressin, epinephrine (α1)
    • full list given in G-protein-linked 2nd messengers topic
 
cGMP signalling
  • Pathway
    • hormone binds to receptor on cell membrane
      • there is also a soluble receptor in the cytoplasm
    • receptor has intrinsic guanylate cyclase activity
      • GTP → cGMP
        • cGMP activate protein kinase G
          • protein kinase G mediates smooth muscle relaxation/vasodilation
      • no G protein required
  • Examples
    • ANF → cell membrane receptor
    • NO → diffuses across cell membrane and binds soluble receptor
      • mechanism for pharmacologic nitrates (nitroprusside, nitroglycerine)
 

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Questions (1)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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