Transduction of Extracellular SignalsTransduction of Extracellular Signals

• Specific receptors in plasma membranes respond to external chemicals (ligands) that cannot cross the membrane: hormones, neurotransmitters, growth factors

• Signal is passed through membrane protein transducer to a membrane-bound effector enzyme

• Effector enzyme generates a second messenger which diffuses to intracellular target

General mechanism of signal transduction General mechanism of signal transduction across a membraneacross a membrane

Regulation of Hexose TransportersRegulation of Hexose Transporters

• Glucose enters mammalian cells by passive transport down a concentration gradient from blood to cells

• GLUT is a family of six passive hexose transporters

• Glucose uptake into skeletal and heart muscle and adipocytes by GLUT 4 is stimulated by insulin

• Other GLUT transporters mediate glucose transport in and out of cells in the absence of insulin

D. Receptor Tyrosine Kinases D. Receptor Tyrosine Kinases (TK)(TK)

• Many growth factors operate by a signaling pathway involving a tyrosine kinase

• TK is a multifunctional transmembrane protein containing a receptor, a transducer, and an effector

• Binding of a ligand to the extracellular receptor domain activates tyrosine kinase (intracellular)

• Activation of receptor tyrosine kinases by ligand-induced dimerization

• Phosphorylated dimer phosphorylates cellular target proteins

• Each domain catalyzes phosphorylation of its partner

Insulin receptor and tyrosine kinase activityInsulin receptor and tyrosine kinase activity

• Insulin binds to 2 extracellular -chains

• Transmembrane -chains then autophosphorylate

• Tyrosine kinase domains then phosphorylate insulin-receptor substrates (IRSs) (which are proteins)

Insulin-stimulated formation of PIPInsulin-stimulated formation of PIP33

Regulation of glucose Regulation of glucose transport by insulintransport by insulin

Insulin Resistance and Type II Diabetes

Normal Conditions: Insulin signaling results in glucose transporter(GLUT-4) translocation from intracellular storage sites to the cellmembrane (muscle, adipose tissue).

Type I Diabetes – insulin dependent, the lack of insulin due to thedestruction of pancreatic ß-cells

Insulin Resistance – the inability of maximal concentrations of insulin to appropriately stimulate muscle glucose transport and other physiological responses.

Type II Diabetes – insulin independent, a global disorder of insulin signal transduction that ultimately disregulates gene expression and cell function in wide range of tissues.

Complications: neuropathy, nephropathy, retinopathy