ch 15: signal transduction

• Types of intercellular signaling include endocrine, paracrine, autocrine, and juxtacrine signaling

  
• There are two types of receptors: cell-surface receptors and intracellular receptors
• Endocrine signaling involves messenger molecules reaching their target cells through the blood stream
• Paracrine signaling: messenger molecules travel short distances through extracellular space

  
• autocrine signaling: cell has receptors on its surface that respond to the mesenger

  
• juxtacrine signaling: short range but requires physical contact between sending and receiving cells

  
• Cell surface receptors are used for hydrophilic signaling molecules that are unable to penetrate the plasma membrane

  
• Intracellular receptors are used by small hydrophobic signaling molecules that can diffuse across the plasma membrane

  
• Second messengers are small substances generated by some cell surface receptors that activate or inactive specific proteins
• Some surface receptors recruit proteins to their domains at the plasma membrane instead of using second messengers
• The first messenger is always a ligand, while the second messenger is a small molecule that increase or decrease concentration in response to the first messenger
• Kinases phosphorylate, while phosphatases dephosphorylate
• Phosphorylation is the addition of phosphate groups to hydroxyl groups such as serine, threonine and tyrosine
• Phosphorylation changes a protein and can induce conformational changes to alter ligand binding and increases or decrease its activity
• Phosphorylation is part of almost all signalling pathways
• GTPase superfamily are a group of enzymes that hydrolyze GTP to GDP
• Signals are often amplified, a small amount of ligand can illicit a large response from a target cell

  
• Ligand-gated ion channels conduct a flow of ions across the plasma membrane to change its potential

  
• G protein-coupled receptors contain alpha helices and activate GTP-binding proteins

  
• Receptor kinases dimerize and activate their cytoplasmic protein kinase domain to phosphorylate specific tyrosine residues of cytoplasmic substrate proteins

  
• Nuclear receptors function as ligand-regulated transcription factors

  
• G protein-coupled receptor: G-protein couples to a receptor with 3 subunits (alpha, beta, and gamma)
• The alpha unit of a G-protein coupled receptors is a GTPase, homologous to ran and rho and all other GTPases
• G-protein coupled receptor include 7 transmembrane a helices, ligand binding site, cytosolic porton, and GRK phosphorylation sites

  
• Ligand binding to the receptor extracellular domain changes the conformation of its intracellular domain, increasing the receptor's affinity for G proteins increases, and the receptor binds the trimeric G protein while a GDP is exchanged for a GTP on the alpha g unit
• Desensitization: blocking active receptors from turning on additional G proteins
• G protein coupled receptor kinase (GRK) phosphorylates GPCR
• Proteins called arrestins compete with G proteins to bind GPCRs

  
• Resensitized: recycling and return of receptors to the cell surface so that the cell remains sensitive to the ligand

  
• G-protein activate adenylyl cyclase by removing two phosphates as pyrophosphate, which is driven by the hydrolysis of pyrophosphate
• cAMP is short-lived and hydrolyzed to 5'-AMP

  
• First messenger: ligand
• Phosphorylates target proteins on their serine or threonine residues
• PKA phosphorylates the appropriate substrates in response to a particular stimulus in a particular cell type
• A kinase anchoring proteins (AKAP) are use to confine PKA to one part of the cell and its signal
• AKAP5 functions as a scaffold protein and is used to confine the PKA signal

  
• AKAPs provide a structural framework or scaffold for coordinating protein-protein interactions by sequestering PKA to specific cellular locations
• Relevant substrates close to AKAPS are the first to become phosphorylated
• Different cells express different AKAPS, resulting in localization of PKA in the presence of different substrates
• Kinases phosphorylates, while phosphatases dephosphorylate