Transcript Slide 1
BIOC 460 - DR. TISCHLER LECTURE 23 SIGNAL TRANSDUCTION: INSULIN OBJECTIVES 1. Structures of proinsulin and insulin; significance of C-peptide. 2. Mechanism for stimulation of insulin secretion and synthesis by glucose by increasing intracellular calcium. 3. Insulin receptor a) key structural features of the b) steps for activation of tyrosine kinase of insulin receptor; the role of interchain autophosphorylation of tyrosine residues c) three intracellular proteins phosphorylated by tyrosine kinase. 4. Mechanism by which insulin mobilizes GLUT-4 transporter to muscle/fat cell plasma membrane via IRS, p85 and PI-3K. 5. Compare causes of type I and type II diabetes; what is meant by insulin resistance in the type II form. C-peptide NH3+ -S S - -S -S -S S- COO- C-peptide secreted with insulin and cleared into the urine NH3+ -S S - -S -S -S SCOO- PROINSULIN INSULIN In the pancreatic -cell preproinsulin is processed to proinsulin and then to insulin that is secreted Figure 1. The structural features of proinsulin and insulin Secreted insulin + C-peptide DAG Protein kinase C IMMEDIATE SECRETION 6 Ca2+ Glucose Ca2+ G L U T 2 1 5 INSULIN BIOSYNTHESIS AND PROCESSING 2 METABOLISM 3 ATP Calmodulin CaM-kinase 4 Figure 2. Control of insulin synthesis and secretion by glucose. CaM kinase: calmodulin-dependent protein kinase; DAG: diacylglycerol + 3H NH3+ N SS Insulin S S -S-S- -subunits Insulin binding: negative cooperativity EXTRACELLULAR -OOC + 3HN S S S S COO NH3+ Plasma membrane Transmembrane domain Tyrosine kinase CYTOPLASM domain -OOC COO-subunits Figure 2. The insulin receptor. Insulin binding to the -chains transmits a signal through the transmembrane domain of the -chains to activate the tyrosine kinase activity Extracellular 2 1 IRTK (L) insulin activated binds L IRTK (R) 3 phosphorylated/ activated OP OP R P P Cytoplasm P P P ATPs ADPs Phosphorylation catalyzed by IRTK (L) Figure 4. Activation of the tyrosine kinase domains of the insulin receptor by insulin binding, followed by interchain autophosphorylation Extracellular 2 1 IRTK (L) insulin activated binds L IRTK (R) 3 phosphorylated/ activated 4 IRTK (L) phosphorylated PO OP OP R ATPs P Cytoplasm P P PO P OP OP P P ADPs ATPs ADPs Phosphorylation catalyzed by IRTK (L) Phosphorylation catalyzed by IRTK (R) Figure 4. Activation of the tyrosine kinase domains of the insulin receptor by insulin binding, followed by interchain autophosphorylation Control of the Insulin Receptor 1) Insulin binding and subsequent dissociation 2) Autophosphorylation to activate 3) Serine phosphorylation to inactivate Figure 5. Intracellular action of insulin Glucose Extracellular GLUT-4 Glucose transport Activated (muscle/adipose) metabolic responses Activation of protein phosphatase leads to dephosphorylation of enzymes in glycolysis, glycogen metabolism, Cell growth lipogenesis, and replication cholesterol synthesis PO IRTK PO Cytoplasm Signal transduction (e.g., IRS, SHC, PLC phosphorylation) KINASE CASCADE (protein phosphorylation) NUCLEUS DNA synthesis Protein synthesis OP OP mRNA synthesis Mitogenic response Extracellular space = GLUT-4 Cytoplasm Active IRTK IRS PO PO OP OP tyr-OH ATP [1] IRTK Figure 6. Hypothetical mechanism for insulin to mobilize GLUT-4 transporter to the plasma membrane in muscle and adipose tissue. IRS, insulin-receptor substrate; IRTK, insulin receptor tyrosine kinase; PI-3K, phosphatidyl-inositol kinase; PDK; phospholipid-dependent kinase PKB, protein kinase B catalyzed IRS p85 [2] activated by docking IRS PIactive IRS tyr-OP IRS 3K IRS IRSactive tyr-OP PIP2 PIP IRS 3 tyr-OP tyr-OP tyr-OP + [4] signals Golgi to traffic GLUT-4 to PDK PKB membrane ADP GOLGI Step 5 Receptor inactivation Step 6 translocation back to Golgi Glucose Step 4 Glucose transport Step 2 Golgi translocation From Golgi (signal) Step 3 Binding and fusion P- -P glucose transporter Step1 - insulin binding and signal transduction Figure 7. Insulin stimulated glucose transport (GLUT-4) in adipose or muscle cells Type I versus Type II Diabetes Type 1 Autoimmune destruction of pancreas -cells Lost ability to produce insulin Requires life-long insulin injection Lack of treatment leads to hyperglycemia Generally begins in children but may not appear until 20’s Type 2 Initiated by reduced ability to respond to insulin Loss of ability to produce insulin Hyperglycemia despite high blood insulin = insulin resistance Generally begins in adulthood but is increasingly seen in teen and pre-teen years Potential to be a major epidemic