Chapter 14 Notes

Description

Cell and Molecular Final
saranilsson47
Note by saranilsson47, updated more than 1 year ago
saranilsson47
Created by saranilsson47 almost 10 years ago
48
1

Resource summary

Page 1

Chapter 14: Signal Transduction Mechanisms: II. Messengers and Receptors 

Different Types of Chemical Signals can be Received by Cells 

Endocrine signals- produced a great distance from their target tissues and are carried out by the circulatory system to various sites in the body (hormones) Paracrine signals- released locally where they diffuse to act at short range on nearby tissues (growth hormones)  Juxtacrine signals- when signals are passed at such a short range that they require physical contact between the sending and receiving cells  Autocrine signals- local mediators that act on the same cell that produces them  Receptors- on the surface of target cells; messenger binds to them and initiates signaling process Ligand- a molecule coming from either a long or short distance and binds to the receptor  Ligands bind to receptor embedded in plasma membrane or binds to a receptor inside the cell. Ligand is the primary messenger  Second messengers- small molecules or ions that relay the signals from one location in the cell to the interior of the cell initiating a cascade of changes within the receiving cell- can affect expression of specific genes  Signal transduction- the ability of a cell to translate a receptor ligand interaction to changes in its behavior or gene expression Many messengers are hydrophilic compounds- functions lies entirely in their ability to bind to one or more specific receptors on a target cell  Hydrophobic messengers- act on receptors in the nucleus or cytosol whose function is to regulate the transcription of particular genes (steroid hormones and retinoids)

Questions: Where do ligands come from?

Summary: There are different types of signals received by cells. Each have their own unique function to help transduce a signal.  

Receptor Binding Involves Specific Interactions between ligands and their receptors 

Highly specific way in which the messenger molecule binds to the receptor  Messenger forms non-covalent bonds with the receptor protein  Individual non-covalent bonds are generally weak; therefore, several bonds must form to achieve strong binding  Within the ligand-binding site on the receptor, appropriate amino acid side chains must be positioned so that they can form chemical bonds with the messenger molecule  The amount of receptor that is occupied by ligand is proportional to the concentration of free ligand in solution.  As ligand concentration increases more and more of its cognate receptors become occupied until most are (saturation)  Further increases in ligand concentration will have no further effect on the target cell

How do cells distinguish messengers from the multitude of other chemicals in the environment or from messengers intended for other cells?

Summary: The combination of binding site shape and the strategic positioning of amino acid side chains within the binding site is what enables the receptor to distinguish its specific ligand from thousands of other chemicals 

Receptor Affinity 

The relationship between the concentration of ligand in solution and the number of receptors occupied is receptor affinity  High affinity for ligand- when almost all of receptors are occupied at low concentrations of free ligand  Low affinity for ligand- when it takes a relatively high concentration of ligand for most receptors to be occupied Dissociation constant (Kd)- the concentration of free ligand needed to produce a state in which half of the receptors are occupied  Values of Kd range from 10^-7 to 10^-10 M tells us at what concentration a particular ligand will be effective in producing a cellular response  High affinity- small dissociation constant Low affinity- high dissociation constant  Co-receptors- help facilitate the interaction of the receptor with its ligand through their physical interaction with the receptor. Provide another layer of regulation of receptor-ligand interactions 

Importance of Kd value

Are there any graphical representations of this?

Summary:A receptor can have either  a high affinity for a ligand or a low affinity depending on the concentration of the ligand in relationship to the receptors. The Kd value shows us what concentration a particular ligand will be effective in producing a cellular response. 

Receptor Down-Regulation

receptors have a characteristic high affinity for ligands cells are geared to sense changes in ligand concentration rather than fixed ligand concentration  to further stimulate the cell the ligand concentration must be increased- receptor down-regulation two main ways in which an adaptation occurs 1st- cells can change the density of receptors on their surfaces in response to a signal  removal of receptors takes place through receptor-mediated endocytosis (invaginate and internalize receptors) results in a diminished cellular response to ligand  2nd- desensitization: involves alterations of the receptor that lower its affinity for ligand or render it unable to initiate changes in cellular function  desensitization allows cells to adapt to permanent differences in levels of messenger concentrations  common desensitization method= addition of phosphate groups to specific amino acids within the cytosolic portion of the receptor (Beta adrenergic receptor)  Drugs that activate the receptor to which they bind are known as agonists  antagonists- inhibit the receptor preventing the naturally occurring messenger from binding and activating the receptor 

Receptor Binding Activates a Sequence of Signal Transduction Events within the Cell

binding of cognate receptor- receptor is altered in a way that causes changes in cellular activity  either induces a change in receptor conformation or causes receptors to cluster together 

Signal Integration 

How do cells respond to such complexity?  Cells must integrate these signals to produce coordinated responses to their environment  Pathways interact with one another because components of one pathway affect the ability of another pathway to transmit its signals  Sometimes a single receptor can activate multiple pathways and in other cases different pathways converge onto the same molecules; second messengers are good examples of such "signal integrators"  signaling cross-stalk: different ligands bind their corresponding receptors at the cell surface, activating specific signaling pathways within the cells. Activated components from one pathway then affect components in another. 

Signal Amplification 

exceedingly small quantities of a ligand are often sufficient to elicit a response from a target cell, yet the responding cell acts in dramatic ways  strong response of target cell results from a signaling cascade with the responding cell - multiply effects of a single receptor-ligand interaction on the cell surface as the signal cascades.  ex: the breakdown of glycogen in the liver cells in response to the hormone epinephrine 

G Protein Linked Receptors Many Seven-membrane spanning receptors act via G proteins 

ligand binding causes a change in receptor conformation that activates a particular G Protein  portion of the activated G protein in turn binds to a target protein such as an enzyme or a channel protein altering the target's activity  hormones norepinephrine olfactory, heroin and morphine

The Structure and Regulations of G-Protein linked receptors 

G protein linked receptors have similar structure yet differ significantly in their amino acid sequences  Each forms seven trans-membrane alpha helices connected by alternating cytosolic or extracellular loops  N-terminus of the protein is exposed to extracellular fluid while the C-terminus resides in the cytosol  The extracellular portion has a unique messenger-binding site and the cytosolic loops allow the receptor to interact with only certain types of G proteins  Regulated in several ways 1.) phosphorylation of specific amino acids in their cytosolic domain- when amino acids are phosphorylated the receptor becomes desensitized  Class of proteins that carry out this function oh phosphorylation are G-protein linked receptor kinases (GRKs)- specifically act on activated receptors  when specific amino acids within the cytosolic portion of receipts such as beta adrenergic receptor are heavily phosphorylated by GRKs a protein known as Beta-arrestin can bind to them and completely inhibit their ability to associate with G proteins  protein kinase A (PKA) which is itself activated by G-protein mediated signaling can phosphorylate other amino acids on the receptor- good example of negative feedback 

The Structure, Activation, and Inactivation of G Proteins 

on and off switch depends on whether the G protein is bound to GTP or GDP two distinct classes of G Proteins: large heterotrimeric G Proteins and small monomeric G proteins large heterotrimeric- contain three different subunits called G alpha G beta and G gamma. Mediate transduction through G protein linked receptors  small monomeric- Ras  in heterotimer G alpha (the largest) binds to guanine nucleotide (GDP or GTP)  When G alpha binds to GTP it detaches from the Gbetagamma complex. G beta and G gamma are permanently bound together  Gs act as stimulators of signal transduction and Gi act to inhibit signal transduction 

when a messenger binds to a G protein linked receptor on the surface of the cell the change in conformation of the receptor causes the G protein to associate with the receptor which in turn causes the G alpha subunit to release its bound GDP  G alpha then requires a new different molecule of GTP and detaches from the complex  either the free GTP-G alpha subunit or the Gbetagamma complex can initiate signal transduction events in the cell  The activity of a G protein exists only as long as the G alpha subunit is bound to GTP and the G alpha and Gbetagamma subunits remain separated  Because G alpha catalyzes GTP hydrolysis it remains active only until it hydrolyzes its associated GTP to GDP at which time it re-associates with Gbetagamma- allows signal transduction pathway to shut down when the messenger is unitized  Some G alpha proteins are very inefficient at catalyzing GTP hydrolysis- efficiency is dramatically improved by regulators of G protein signaling proteins (RGS)  when RGS binds G alpha they stimulate GTP hydrolysis  GTPase activating proteins are important regulators of G protein functions  two widely used second messengers are cyclic AMP and calcium ions which stimulate the activity of target enzymes when their cytosolic concentrations are elevated 

Cyclic AMP is a Second Messenger whose production is regulated by some G proteins 

Cyclic AMP is formed from cytosolic ATP by the enzyme adenylyl cyclase  adenylyl cyclase is anchored in the plasma membrane with catalytic portion protruding into the cytosol  normally it is inactive until it binds to an activated G alpha subunit of a specific G protein such as Gs when G protein linked receptor is coupled to Gs the binding of ligand stimulates the Gsa unit to release GDP and acquire a GTP  causes GTP-GSa to detach from the GSby subunits and bind to adenylyl cyclase  when binds to adenylyl cylcase the enzyme becomes active and converts ATP to cAMP  Gia inhibits the adenylyl cyclase  G proteins respond quickly to changes because they remain active only for short time before the G alpha subunit hydrolyzes GTP and converts to the inactive state  onces becomes inactive the adenylyl cyclase ceases to make cAMP  cAMP would remain elevated in the cell if it weren't for phosphodiesterase- degrades cAMP (further ensures that the signal transduction will be shut down)  cAMP important for many cellular events- glycogen degradation fatty acid production heart rate blood pressure, water reabsorption, bone resorption  cAMP has one main intracellular target- the enzyme protein kinase A PKA phosphorylates by transferring a phosphate from ATP to a serene or threonine found within the target protein  cAMP regulates the activity of PKA by causing the detachment of its two regulatory subunits from its catalytic subunits  once catalytic submits are free PKA can catalyze the phosphorylation of various proteins in the cell  increase in cAMP in skeletal and liver cells the breakdown of glycogen is stimulated. increase in cardiac muscle strengthens heart contraction whereas the smooth muscles contraction is inhibited 

Disruption of G Protein Signaling causes several human diseases 

What would happen if the G protein adenlyl cyclase system could not be shut off?  Bacteria Vibrio choleraw and Bordetella pertussi both cause disease through their effects on heterotrimeric G proteins  Cholera results from the secretion of cholera toxin when V. cholera colonizes in the gut. the toxin alters the secretion of salts and fluid in the intestinal lumen which is normally regulated by hormones that act through G protein Gs to alter intracellular levels of cAMP- no loner hydrolyze GTP to GDP so Gs cannot be shut off and cAMP levels remain high so intestine secretes large amounts of salt and water  pertussis toxin acts on the Gi which normally shuts off adenlyl cyclase- so no longer inhibits adenlyl cyclase so fluid accumulates in the lungs 

Many G proteins use inositol triphosphate and diaclyglycerol as second messengers 

inositol phospholipids product= inositol-1,4,5-triphosphate (IP3) functions as a second messenger  generated when the enzyme phospholipase C is activated and cleaves PIP2 into two molecules: inositol triphosphate and diaclyglycerol (DAG)  Roles of IP3 and DAG as second messengers in calcium pathway  Begins with binding of ligand to its membrane receptor leading to activation of as specific G protein called Gq. Gq then activates a specific phospholipase C known as Cb generating both IP3 and DAG  Inositol triphosphate is water soluble and quickly diffuses through the cytosol binding to a ligand-gated calcium channel known as the IP3 receptor channel in the ER  When IP3 binds the channel opens releasing calcium ions into the cytosol  intracellular calcium release as well as formation of DAG by phospholipase C activity activates members of the protein kinase C (PKC)- can then phosphorylate specific serene and threonine groups on a variety of target proteins  IP3 stimulated calcium release and DAG mediated kinase activity are both required to produce a full response in target cells 

The release of calcium ions is a key event in many signaling processes 

ligand binding leads to an increase in IP3 concentration which in turn triggers an increase in cytosolic calcium concentrations increase in calcium concentrations were linked to the physiological response of salivary secretion  calcium ionophore- renders membranes permeable to calcium thereby releasing intracellular stores of calcium in the absence of physiological stimulus  treatment of calcium ionophore mimicked the effect of IP3 thus implicating calcium as the intermediary in the IP3 signal transduction pathway  calcium ATPases- maintains relatively low levels of calcium in the cytosol ( located in plasma membrane and ER)  calcium ATPases in the plasma membrane transport calcium out of the cell whereas the calcium ATPases in the ER sequester calcium ions in the lumen of the ER  sodium-calcium exchangers- further reduce the cytosolic calcium concentration  mitochondria- can transport calcium into the mitochondria matrix  cytosolic calcium concentrations to increase- opening of calcium channels in the plasma membrane (calcium ions rush into the cell) can also be elevated by the release of calcium from intracellular stores 

Calcium release following fertilization of animal eggs 

exocytosis is regulated by calcium  fertilized eggs is an example of calcium mediated signal transduction  release of calcium from sperm cells results in their activation  early response of the egg is release of calcium from internal stores  calcium release initially occurs at the site where the sperm penetrates the egg via calcium induced calcium release  calcium release is necessary for two crucial events 1st- stimulates the exocytosis of vesicles (cortical granules) resulting in alterations of the protein coat surrounding many eggs- render the egg unable to bind additional sperm (slow block to polyspermy)  2nd- egg activation- resumption of many metabolic processes reorganization of the internal contents of the egg 

Calcium binding activates many effector proteins 

calcium can bind directly to many different effector proteins altering their activity  the response of a target cell to increase calcium depends on the particular calcium binding proteins that are present  calmodulin protein- mediates calcium activated events in the cell (arm with hand at each end)  two calcium ions bind at each of two hand regions causing the calmodulin to undergo a change in shape that forms the active calcium calmodulin complex.  when a protein is present that contains a calmodulin binding site such as a protein kinase or phosphatase the hand and arm bind to it by wrapping around the binding site - calmodulin can influence the function of such a protein dramatically  calmodulin has affinity for calcium- binds to calcium when the cytosolic calcium concentrations increase to about 1.0um but releases calcium when cytosolic calcium levels decline back down to the resting level of .1um 

The By subunits of G proteins can also transduce signals

G protein receptor kinases can be activated by the By subunit of the dissociated G protein providing a feedback mechanism on G protein signals  muscarinic acetylcholine receptor- when acetylcholine binds to muscarinic acetylcholine receptor the By subunit of its dissociated G protein (Gi) acts on potassium channels in the plasma membrane causing them to open  when acetylcholine is no longer present the alpha and By subunits re-associate causing the potassium channels to close again  in yeast- By subunits initiate a series of phosphorylation events that lead to activation of a type of kinase known as MAP kinase 

Other signaling Pathways can Activate G Proteins 

many other pathways can lead to the activation of heterotimeric G proteins  these include Wnts (act through seven pass receptors known as Frizzleds) and the Hedgehog pathway which acts in part through another seven pass protein known as smoothened 

Protein Kinase Associated Receptors 

protein kinases transmits signals when bind to appropriate ligand their kinase activity is stimulated and they transmit signals through a cascade of phosphorylation events within the cell  kinases add phosphate groups to particular amino acids within substrate proteins  two major categories:  those that phosphorylate a tyrosine residue and those that phosphorylate a serine or threonine residue 

Growth Factors often Bind protein kinase-associated receptors 

protein kinase-associated receptors play a roll in cell proliferation  for a cell to divide it must have all the nutrients needed for synthesis of its component parts but the availability of nutrients is usually not sufficient for growth  blood serum not plasma supports the growth of cells  many messenger in serum are members of class of proteins known as growth factors  plasma is whole loos including unreacted platelets but without the red and white blood cells  serum is the clear fluid remaining after blood has clotted  during clotting platelets secrete growth factors into the blood that stimulate the growth of cells called fibroblasts which form the new connective tissue that make up a scar  after clotting resulting serum is full of platelet derived growth factor (PDGF) plasma does not contain this factor because the clotting reaction has not taken place  receptor for PDGF is tyrosine kinase  several growth factors act by stimulating receptor tyrosine kinases  growth factors function for growth and cell division as well as crucial events during the development of embryos, responses to tissue injury, and many other activities  growth factors are secreted molecules that act at short range and have specific effects on cells possessing the appropriate receptor to sense the presence of the growth factor. 

Receptor Tyrosine Kinases Aggregate and undergo autophosphorylation 

receptor tyrosine kinases (RTKs) trigger a chain of signal transduction events that lead to cell growth proliferation or the specialization of cells  examples: insulin receptor, the nerve growth factor receptor, and the epidermal growth factor receptor 

The structure of receptor tyrosine kinases 

receptors often consist of a single polypeptide chain with only one transmembrane segment  within polypeptide chain are several distinct domains  extracellular portion contains the ligand binding domain the other end of the peptide protrudes through the plasma membrane into the cytosol  on the cytosolic side a portion of the receptor forms the tyrosine kinase  the cytosolic portion of the receptor contains tyrosine residues that are in fact targets for the tyrosine residue portion of the receptor  in some cases the receptor and the tyrosine kinase are two separate proteins; the tyrosine kinase is then referred to as a non receptor tyrosine kinase- it can bind to a receptor and be activated when the receptor binds to the ligand  non-receptor tyrosine kinase- Src protein which is encoded by the src gene of the avian sarcoma virus 

The activation of receptor tyrosine kinases 

signal transduction is initiated when the ligand binds causing the receptor tyrosine kinases to aggregate  two receptor molecules aggregate together within the plasma membrane when the bind ligand once the receptors cluster in this way the tyrosine kinase associated with each receptor phosphorylates the tyrosine's of neighboring receptors.  since the receptors phosphorylate other receptors of the same type this process is called autophosphorylation 

Receptor tyrosine kinases initiate signal transduction cascade involving RAS and MAP kinase 

RTK signal transduction is different form G protein transduction 1. autophosphorylation of tyrosine residues on the cytosolic portion of the receptor occurs in response to ligand binding  2. receptor recruits a number of cytosolic 

Chapter 14

New Page

New Page

Show full summary Hide full summary

Similar

RNA Viruses
ravi shah
Non-Arboviruses
Nicolette Adamson
Micro Exam 1
stephdancer8
HIV-1 Including Current and Future Treatment Strategies
Matthew Coulson
Pendahuluan dan Sejarah Virologi
raifedora
MMI Module Exam Unit 3 and 4
jamiec2119
microbiology
atbaa 2020
The Course of Viral Infections
gina_evans0312
Herpes Viruses and Cancer
gina_evans0312
EBV Infection
gina_evans0312