CHAPTER 11 cell signaling Local regulators Ex) growth factors – paracrine signaling and synaptic signaling Long distance signaling - Hormones (insulin, ethylene) - nervous system

3 stages of signaling Earl Sutherland (1971) Epinephrine and glycogen breakdown Reception – binding to signal receptor Transduction-often a series of changes (signal transduction pathway) Response-end result – a specific cellular response

Receptor types I. Bound to plasma membrane G protein couple receptors Receptor Tyrosine Kinases Ion channel receptors II. Intracellular Located in cytosol or nucleus require hydrophobic or small messengers Steroid hormones, thyroid hormones, NO

Membrane receptors up close G Protein-Coupled receptors widespread, very common, involved with neurotransmitters(nervous), many hormones (epinephrine), and embryonic development Involves G protein and GTP

G protein (cytoplasmic side) is off when bound to GDP Ligand binds to extracellular side of receptor Receptor is actived (shape) and binds to G protein GTP replaces GDP on G protein G protein binds to and activates an enzyme G protein hydrolyzes GTP to GDP (GTPase) and returns to start

Receptor Tyrosine Kinases kinases transfer phosphate groups Involved with enzymatic activity Ex. Growth hormone binding/response

Individual receptor tyrosine kinase proteins bind a signaling molecule (ligand) Tyrosine kinase proteins form a dimer This activates the kinase region of each, and each tyrosine kinase phosphorylates its tyrosines via ATP Once activated, it is recognized by relay proteins in cell and binds them Often activates multiple pathways

Ion Channel Receptors Involves gated responses involving ion flow Ex) neurotransmitters (ligands) and neurons (action potentials) Ions flowing across membranes create currents

Ligand binds to channel receptor while receptor is in closed conformation Receptor changes shape to open gate Very specific ion(s) begin to flow down their electrochemical gradient This flow of ions affects cell function Ligand dissociates, ending the process

Intracellular receptor model Results in gene expression (ex. Testosterone effects) Steroid hormone passes through plasma membrane and binds to receptor protein in cytoplasm Activated receptor protein enters the nucleus and acts as a transcription factor for a particular gene

Cascading………. Can greatly amplify the signal to numerous molecules at each step *usually involves “phosphorylating” proteins a)protein kinase – transfers phosphates to other proteins(targeting serine or threonine)

b) Protein phosphatase – de-phosphorylates proteins, making them available again and terminating the signal.

Second Messengers Involves small, non-protein , water soluble molecules or ions Focus: cyclic AMP (cAMP) and Calcium(Ca++)

cAMP figure 11.10/11.11 1. Epinephrine binds to receptor protein 2. Receptor activates “adenylyl cyclase” which converts many ATP to cAMP 3. cAMP is short lived due to “phosphodiesterase”, which converts cAMP to AMP 4. Some G protein pathways can inhibit adenylyl cyclase

Calcium Typically low in cytosol (why?) IP3 (inositol triphosphate) acts before Calcium FIGURE 11.13 Calcium ions are involved in muscle contractions and neurotransmitter release

FINE tuning Signal Amplification – a small amount of signaling molecule can cause large changes Different responses to same signaling molecule (epinephrine) Signaling efficiency – scaffolding proteins – pathways are often complex, not linear(11.18) Termination is necessary

APOPTOSIS -programmed cell death via “digestion” (internally and externally) Signal can be external (from other cells) or internal from nucleus or ER Proteins for such events are always present, but inactive Caspases are proteases of apoptosis

C. elegans (nematode) ced-3 and Ced-4 genes for appropriate apoptosis proteins

Learning outcome Objectives: 1) students will be able to relate cell differentiation and specialization to different cellular responses to a particular ligand. 2) Students will be able to discuss various mechanisms by which cells can communicate with other cells via signaling molecules.

Multiple choice One major characteristic of cell signaling is that the pathway must be able to be “turned on and shut off” when needed. Which pathway involves an activation mechanism not initiated by the binding of a ligand to and external cellular receptor? a) the phosphorylation of tyrosines b) the opening and closing of voltage regulated ion channels c) reception of a hormone to form a transcription factor d) the binding of GTP to activate a G protein

Open Response a) Discuss the three stages of “cell signaling.” b) Explain how just one particular ligand can ultimately stimulate different types of body cells to respond in very different ways. Also, describe why some body cells might not respond at all to a given ligand.