Transduction 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 across a membrane

Regulation 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 (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 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 PIP 3

Regulation of glucose transport 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 cell membrane (muscle, adipose tissue). Type I Diabetes – insulin dependent, the lack of insulin due to the destruction 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