Learning Objectives Number 4OceanSee the review sheet on MoodleCell Signaling What are first messengers?- Direct contact; short distance signaling- Extracellular molecule that elicits a cellular response when it binds to a receptor protein- E.g. hormones, neurotransmittersWhat are two examples of second messengers?- Non-protein, water soluble molecules or ions- cAMP and Ca+2- cAMPo synthesized from ATPo activates an enzyme called protein kinase- Ca+2o Muscle contractionsWhat is signal amplification and how does it benefit the cell?- Signal amplification is amplifying the cells response to a signal by phosphorylating the cascades of enzymes and cAMP molecules.- Amplify faint signalo A few “first messenger” moleculeso Many second messengerso Each step in the cascade recruits more molecules- Elicits a coordinated responseWhat is the role of phosphorylation cascades in signal amplification?- Phosphorylation cascades—activated kinase activates a different kinase, etc. - At each step more enzymes are recruitedWhere are the receptors involved in cell signaling located? - On the cells surface or inside of the cell- Plasma membraneo Integral membrane proteins- Intracellular receptoro E.g. steroid hormone receptorsSignal amplification in the breakdown of glycogen - Epinephrine (adrenaline) activates a GPCR in liver cells (e.g., Fig. 11.10, 11.16, 45.7 and 45.9)- Calcium activates a phosphorylation cascade in skeletal muscle (after the Protein Kinase A step in Fig 11.16, activating the enzyme phosphorylase kinase)- As a result of signal amplification, a small number of epinephrine molecules binding to receptors on the surface of a liver cell or muscle cell 1can lead to the release of hundreds of millions of glucose molecules from glycogen. The relationship of adenylyl cyclase and cAMP- Adenylyl cyclase catalyzes the formation of many cAMP molecules from ATPHow is adenylyl cyclase activity regulated?- Epinephrine outside the cell binds the receptors on the surface of the cell causing the activation of adenylyl cyclase which in turn can catalyze manymolecules of cAMP.- The enzyme is modulated (positively and negatively) by different G proteins- Intracellular cAMP levels go up or downo Depends on the summation of all the positive and negative signals on the cellWhat reactions do protein kinases and phosphatases catalyze?- Protein kinases: phosphorylation rxnso Covalent transfer of PO3-4 group from ATP to specific amino acids of target proteino Acts as an “on” or “off” switch for the target protein- Phosphatases: remove phosphate groupWhat is the role of cAMP-dependent Protein Kinase (Protein Kinase A) in cell signaling? - Catalyzes phosphorylatin rxnsWhat are the subunits of Protein Kinase A and what do they do? - 2 regualtory subunits- 2catalytic subunits What is the subunit composition of the active enzyme? - In the cytoplasm cAMP binds to the R subunit- R2C2 dissociates into an R dimer and 2 C monomers- C monomers catalyze phosphorylation rxns Of the inactive enzyme?- R2C2Gproteins- “switch” proteins- either “on” or “off”- activated by occupied (activated) receptor- GDP is bound to the alpha subunit of the inactive G protein heterotrimer- Inactive (“off”): a-GDPBy- Active (“on”): a-GTPBy- Activation of G proteinso An activated receptor interacts with the g proteino GTP replaces GDB on the alpha subunito The protein dissociated into alpha-GTP and a By(beta gamma) dimero The g protein is now “on” Then interacts with their target enzymes or ion channels2o Turned “off” when an intrinsic GTPase activity of the alpha subunit hydrolyzes GTP to GDP Alpha-GDP and beta gamma dimer reassociate- membrane receptor is activated by an intracellular signal- G protein transfers extracellular signal into the intracellular compartment by interactive with a target - Target enzyme produces and intracellular “second messenger”What is G protein cycle? Be sure you know all of the steps in the cycle and can reproduce it from memory.What are examples of the types of G proteins?- Gs—stimulatory G proteino Stimulates adenylyl cyclase- Gi—inhibitory G proteino Inhibits adenylyl cyclase- Golf—olfactory protein- Gt—transducin, the G protein involved in visionWhat are the subunits of G proteins?- Alpha- Beta- gammaInhibitory and stimulatory signals and receptorsWhat would happen if the G protein cycle is disrupted by mutations? (see Potential Targets for Disease on Moodle)- loss of function mutations: prevent formation of stable mRNA or protein- gain of function mutations: e.g. activation of receptor in the absence of agonist (first messenger)See the G protein cycle sheet and the work sheet on Moodlefigures 11.5, 11.6, 11.7, 11.9, 11.10, 11.11, 11.12, 11.15 and 11.16. Hormones What is homeostasis? - Steady-state physiological condition- “constancy” of the interior environment of an organismWhat are examples of homeostasis?- E.g. constant pH, body temp, ion concentrationWhat is meant by antagonistic?- Hormones that work against each otherWhat is feedback regulation? (Fig. 45.17)- End product of a pathway inhibits an enzyme in that pathwayWhat is the endocrine system? - Regulatory system that maintains homeostasis through hormones- Consists of hormones and the glands (endocrine glands=ductless glands)which secrete themHow are hormones transported to their targets? - Endocrine glands secrete hormones into the blood streamChem classification of hormones (fig 45.5.)3What makes a cell a target for a particular hormone?- Have receptors for specific first messengers- Differet cell types will have a different profile of receptorsThe regulation of blood glucose concentrationsWhat are the three hormones directly involved? What do these three hormones do?FIG 45.13- Insulino Lowers bl. Glucose levels- Glucagono Raises bl. Glucose levels- Osteocalcino Makes beta cells in pancreas produce extra insulinWhat chemical class do these hormones belong to? - Peptide hormonesWhere are these hormones produced?- Unsulin and glucagon: pancreas- Osteocalcin: skeleton (bone cells)Know the two types of diabetes discussed in lecture- Type I and Type IIWhat are the underlying causes?o Type I: autoimmune destruction of cells releasing insulin Inability to produce insulino Type II: onset related to obesity and heredity Failure of the signal transduction system to elicit a response to insulin or inadequate insulin productionWhat are the hormones involved in blood calcium
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