11 CAMBELL BIOLOGY TENTH EDITION Reece Urry Cain Wasserman Minorsky Jackson Cell Communication Lecture resentation by Dr Burns NVC Biol 120 Outline I. Cell Signaling II. Forms of cell signaling III. Quick review of cell IV. Cell Surface s I. G- Coupled s II. osine Kinase s III. Control of cell division IV. Ligand-Gated Ion Channels V. Intracellular s VI. Down regulation 2014 earson Education, Inc. Overview: Cellular Messaging Cell-to-cell communication is essential for both multicellular and unicellular organisms Biologists have discovered some universal mechanisms of cellular regulation Cells most often communicate with each other via chemical signals For example, the fight-or-flight response is triggered by a signaling molecule called epinephrine Evolution of Signaling athway similarities suggest that ancestral signaling molecules evolved in prokaryotes and were modified later in eukaryotes The concentration of signaling molecules allows bacteria to sense local population density Local and Long-Distance Signaling Figure 11.4 lasma s Cell wall Cells in a multicellular organism communicate by chemical messengers Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacent cells Gap junctions between animal cells (a) Cell junctions lasmodesmata between plant cells In local signaling, animal cells may communicate by direct contact, or cell-cell recognition (b) Cell-cell recognition 1
Local and Long-Distance Signaling In many other cases, animal cells communicate using local regulators, messenger molecules that travel only short distances In long-distance signaling, plants and animals use chemicals called hormones The ability of a cell to respond to a signal depends on whether or not it has a receptor specific to that signal Forms of Signaling 1. Gap Junctions 2. Autocrine - A cell secretes a molecule that binds back onto its own receptor 3. aracrine - Local mediators 4. Synaptic Nerve cell signal transmission Neurotransmitters, released into synaptic cleft 5. Endocrine - long acting, wide spread Hormones, secreted into the bloodstream Figure 11.5 Local signaling Target cells Electrical signal triggers release of neurotransmitter. Neurotransmitter diffuses across Secreting synapse. cell Secretory vesicles Local regulator Target cell (a) aracrine signaling (b) Synaptic signaling Long-distance signaling Endocrine cell Target cell specifically binds hormone. Hormone travels in bloodstream. The Three Stages of Cell Signaling Earl W. Sutherland discovered how the hormone epinephrine acts on cells Sutherland suggested that cells receiving signals went through three processes Reception Transduction Response (c) Endocrine (hormonal) signaling Blood vessel Figure 11.6-1 Figure 11.6-2 lasma CYTOLASM lasma CYTOLASM 1 Reception 1 Reception 2 Transduction 1 2 3 Relay molecules Signaling molecule Signaling molecule 2
Figure 11.6-3 lasma CYTOLASM 1 Reception 2 Transduction 1 2 3 Relay molecules 3 Response Activation of cellular response Signaling molecule Animation: Overview of Cell Signaling Right-click slide / select lay Reception: A signaling molecule binds to a receptor, causing it to change shape Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell The binding between a signal molecule, the ligand, and receptor is highly specific A shape change in a receptor is often the initial transduction of the signal Most receptors are plasma s Signal transduction usually involves multiple steps Multistep pathways can amplify a signal: A few molecules can produce a large cellular response Multistep pathways provide more opportunities for coordination and regulation of the cellular response Fig. 9.8.b rotein hosphorylation In many pathways, the signal is transmitted by a cascade of phosphorylations rotein kinases transfer phosphates from AT to, a process called phosphorylation 3
rotein Dephosphorylation Fig. 9.3 rotein phosphatases remove the phosphates from s, a process called dephosphorylation This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off or up or down, as required Figure 11.10 Signaling molecule Activated relay molecule kinase 1 Active kinase 1 Which type of ligand would bind to a receptor in the plasma 1. Water soluble 2. Lipid soluble 64% kinase AT 2 AD i Active kinase 2 36% kinase AT 3 AD i Active kinase 3 AT AD i Active Cellular response 1 2 Copyright 2009 earson Education, Inc. The following can freely pass through a : Fig. 9.1 1. Ions 2. Hydrophobic molecules 3. hydrophillic molecules 4. Ions and hydrophilic molecules 0% 50% 25% 25% 1 2 3 4 Copyright 2009 earson Education, Inc. 4
s in the lasma Membrane Most water-soluble signal molecules bind to specific sites on receptor s that span the plasma = cell surface receptors There are three main types of receptors G -coupled receptors tyrosine kinases Ion channel receptors s in the lasma Membrane - GCRs G -coupled receptors (GCRs) are the largest family of cell-surface receptors A GCR is a plasma receptor that works with the help of a peripheral G Figure 11.7a Signaling molecule binding site Segment that interacts with G s G -coupled receptor G roteins Trimeric GT-binding = G roteins G roteins are either in the active or inactive state Active state has GT bound When the ligand binds the G- Coupled, this causes a change in shape, that activates the G rotein This starts a chain of events that involve intracellular mediators = secondary messengers Figure 11.7b Trimeric G roteins G -coupled receptor lasma Activated receptor Signaling molecule enzyme G roteins are composed of three s: α and β and γ subunits CYTOLASM 1 GD G (inactive) Enzyme Activated enzyme 2 GD GT GD GT When the G rotein is activated (GT is bound) the α subunit (with GT) goes one way and the β and γ go together another way. GT 3 Cellular response 4 GD i β and γ are active when they are not attached to the α subunit the α subunit has GTase activity 5
GTase activity in G s The G is active only when it has GT bound to it. The G has GTase activity, which means it will automatically hydrolyze a phosphate and have GD bound. This way it inactivates itself automatically This GTase activity is enhanced by GTase Activating roteins (GAs) Activation and deactivation of G s When the G binds to the GCR, the alpha subunit ejects a GD and accepts a GT. Alpha detaches from beta/gamma subunits, they are now active. After a period of time, the G self hydrolyses a phosphate from the GT, forming GD. Alpha will now reform with beta/gamma subunits, they are now inactive Fig. 9.11 Small Molecules and Ions as Second Messengers The extracellular ligand that binds to the receptor is a pathway s first messenger Second messengers are small, non, water-soluble molecules or ions that spread throughout a cell by diffusion Second messengers participate in pathways initiated by GCRs and RTKs Cyclic AM and calcium ions are common second messengers Cyclic AM Figure 11.11a Cyclic AM (cam) is one of the most widely used second messengers Adenylyl cyclase, an enzyme in the plasma, converts AT to cam in response to an extracellular signal Adenylyl cyclase yrophosphate i AT cam 6
Figure 11.11b Figure 11.12 First messenger (signaling molecule such as epinephrine) G Adenylyl cyclase hosphodiesterase G -coupled receptor GT H 2 O H 2 O AT cam Second messenger cam AM rotein kinase A Cellular responses cam athway 1. A ligand binds to the G- Coupled (GCR). 2. The binding of the ligand (hormone) activates the GCR. 3. The active GCR is able to bind the G- 4. The G- ejects a GD and accepts a GT molecule. The G- is now active 5. The α subunit of the G- with the GT disassociates from the β and γ subunits 6. The α subunit of the G- with the GT goes to adenylyl cyclase and activates it 7. The active adenylyl cyclase transforms AT into cam 8. cam activates a kinase A (KA) 9. cam is inactivated by phosphodiesterases 10. The KA phosphorylates s 11. The phosphorylated s are now active and can change the cell activity 12. The g- with GT bound will hydrolyze the phosphate from GT, now has GD bound and is inactive. It will reform with the β and γ subunits and this inactivates them Fig. 9.13 Fig. 9.16 7
Figure 11.16 Reception Binding of epinephrine to G -coupled receptor (1 molecule) Transduction G Active G (10 2 molecules) adenylyl cyclase Gene transcription by cam The cam pathway can also activate the transcription of specific genes Active adenylyl cyclase (10 2 ) AT Cyclic AM (10 4 ) kinase A Active kinase A (10 4 ) phosphorylase kinase The kinase A (KA) activated by cam can turn on transcription of DNA using a CRE-binding (cam response element) Response Active phosphorylase kinase (10 5 ) Glycogen glycogen phosphorylase Glucose 1-phosphate (10 8 molecules) Active glycogen phosphorylase (10 6 ) Examples of Hormone induced responses mediated by cam Target Tissue Hormone Major Response Adrenal Cortex ACTH Cortisol Secretion Ovary LH rogesterone secretion Muscle Adrenaline Glycogen breakdown Bone arathyroid hormone (TH) Bone reabsorption Heart Adrenaline Increase heart rate Liver Glucagon Glycogen breakdown Kidney Vasopressin Water reabsorption Fat Adrenaline, ACTH, glucagon Triglyceride breakdown Animation: Signal Transduction athways Right-click slide / select lay Calcium Ions as a secondary messenger Figure 11.13 lasma Calcium ions (Ca 2+ ) act as a second messenger in many pathways Calcium is an important second messenger because cells can regulate its concentration CYTOSOL AT Ca 2 pump Mitochondrion Nucleus AT Ca 2 pump Ca 2 pump Endoplasmic reticulum (ER) Key High [Ca 2 ] Low [Ca 2 ] 8
Figure 11.14-3 EXTRA- CELLULAR Signaling molecule (first messenger) G -coupled receptor G GT hospholipase C I 2 DAG I 3 (second messenger) Copyright The McGraw-Hill Companies, Inc. ermission required for reproduction or display. Ca 2+ Ca 2+ Ca 2+ Calmodulin I 3 -gated calcium channel Calmodulin Endoplasmic reticulum (ER) CYTOSOL Ca 2 Ca 2 (second messenger) Various s activated Cellular responses a. b. Active tyrosine kinases (RTK) tyrosine kinases (RTK) hosphorylates tyrosine amino acids on signaling s tyrosine kinases (RTKs) tyrosine kinases (RTKs) are receptors that attach phosphates to tyrosines A receptor tyrosine kinase can trigger multiple signal transduction pathways at once Abnormal functioning of RTKs is associated with many types of cancers osine Kinase These receptors just cross the plasma once single trans s RTKs are dimers it takes two RTKs to function Binding of the ligand causes two RTKs to come together and link to form a dimer = dimerize osine Kinase When the two receptors link together, they now have enzyme activity They phosphorylate tyrosine residues on each other = autophosphorylation This requires AT 9
osine Kinase Ligands Figure 11.7c Signaling molecule (ligand) helix in the Ligand-binding site Signaling molecule Examples of ligands for receptor tyrosine kinases: Insulin Growth hormone Erythropoietin 1 osines CYTOLASM tyrosine kinase s (inactive monomers) 2 Activated relay s Dimer 6 AT 6 AD Activated tyrosine Fully activated kinase regions receptor tyrosine (unphosphorylated kinase dimer) (phosphorylated 3 dimer) 4 relay s Cellular response 1 Cellular response 2 Fig. 9.7 MA Cascades Mitogen-activated kinases (MAK) Mitogens are important in normal cell division MA kinases are a series of kinases that phosphorylate other kinases Ending in a cellular response including gene transcription These cascades amplify the response RTK/Ras/MA athway 1. Two ligands binds to two RTKs (one ligand/receptor) 2. The two RTK dimerize and phosphorylate each other, activating each other 3. The active RTKs activate GRB2 and SOS s activate a GT-binding (G ) called Ras causing it to eject GD and accept GT 4. The now active Ras activates the MA kinase cascade until the MA kinase is activated 5. The MA kinase activates s which leads to cellular activity. 6. Ras will automatically inactivate by dephosphorylating the GT to GD Fig. 9.8.a 10
Fig. 9.8.b The eukaryotic cell cycle is regulated by a molecular control system The frequency of cell division varies with the type of cell These differences result from regulation at the molecular level Cancer cells manage to escape the usual controls on the cell cycle 11
The Cell Cycle Control System Figure 12.15 G 1 checkpoint The sequential events of the cell cycle are directed by a distinct cell cycle control system, which is similar to a clock The cell cycle control system is regulated by both internal and external controls G 1 Control system S The clock has specific checkpoints where the cell cycle stops until a go-ahead signal is received M G 2 M checkpoint G 2 checkpoint The Cell Cycle Control System Figure 12.16 For many cells, the G 1 checkpoint seems to be the most important If a cell receives a go-ahead signal at the G 1 checkpoint, it will usually complete the S, G 2, and M phases and divide G 1 checkpoint G 0 If the cell does not receive the go-ahead signal, it will exit the cycle, switching into a nondividing state called the G 0 phase (a) Cell receives a go-ahead signal. G 1 G 1 (b) Cell does not receive a go-ahead signal. Stop and Go Signs at the Checkpoints Some external signals are growth factors, s released by certain cells that stimulate other cells to divide For example, platelet-derived growth factor (DGF) stimulates the division of human fibroblast cells in culture roto-oncogenes roto-oncogenes art of the DNA that codes for gas pedal s. When proto-oncogenes mutate they become cancer-causing genes called oncogenes. Example of a proto-oncogene = ras gene The ras is a G that relays a signal from a growth factor receptor to a cascade of kinases, the end result of the cascade is a the synthesis of a that stimulates the cell cycle 24-5 12
Ligand-gated ion channel A ligand-gated ion channel receptor acts as a gate when the receptor changes shape When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as Na + or Ca 2+, through a channel in the receptor Important in neuron signal transmission Figure 11.7d Intracellular s 1 2 3 Signaling molecule (ligand) Gate closed Ions lasma Ligand-gated ion channel receptor Gate open Cellular response Gate closed Intracellular receptor s are found in the cytosol or nucleus of target cells Small or hydrophobic chemical messengers can readily cross the and activate receptors Examples of hydrophobic messengers are the steroid and thyroid hormones of animals An activated hormone-receptor complex can act as a transcription factor, turning on specific genes Intracellular s Examples of Intracellular s Lipid soluble and small signaling molecules bind to receptors located inside the cell. Intracellular receptors are located in the cytosol or the nucleus The intracellular receptors in the cytosol will bind with the ligand, the binding will cause the receptor/ligand complex to travel to the nucleus. Steroid hormones Estrogen, testosterone, cortisol Effects gene expression Nitric Oxide (gas) Binds to receptor that is an enzyme = guanylyl cyclase (Viagra works through this pathway) 13
Steroid Hormone Intracellular s These hormones cross the plasma and bind to an intracellular receptor in the cytosol The binding of the ligand to the receptor causes the ligand/receptor to go to the nucleus The ligand/receptor regulates gene expression Intracellular s rior to the ligand binding, the receptor may have s that block the DNA binding domain. The binding of the ligand signals the receptor to go the nucleus and allow the receptor to bind to the DNA Fig. 9.5 Figure 11.9-1 Hormone (testosterone) lasma DNA NUCLEUS CYTOLASM Figure 11.9-2 Hormone (testosterone) Figure 11.9-3 Hormone (testosterone) lasma Hormonereceptor complex lasma Hormonereceptor complex DNA DNA NUCLEUS NUCLEUS CYTOLASM CYTOLASM 14
Figure 11.9-4 Hormone (testosterone) Figure 11.9-5 Hormone (testosterone) lasma Hormonereceptor complex lasma Hormonereceptor complex DNA DNA mrna mrna NUCLEUS NUCLEUS New CYTOLASM CYTOLASM Controlling Cell Signaling To control cell signaling: 1. The G-s have GTase activity 2. Ligand levels fall 3. Ca ++ is sequestered 4. There are phosphatases that inactivate the s that were activated by phosphorylation 5. hosphodiesterases 6. s are internalized http://biochemistry.utoronto.ca/brown/mgy425/egan_tk_ras_2009.ppt#68 15
Important Concepts Know the vocabulary covered in this lecture Know examples of signaling molecules Know the forms of cell signaling Know the main classifications of signaling receptors, what are the main differences and what type of ligands generally bind these receptors, examples of secondary messengers Understand how intracellular receptors work, what are the steps from the binding of a ligand to the cellular activity and what type of activity is regulated by intracellular receptors. Important Concepts Know the classes of Cell Surface roteins What is the function of kinases and phosphotases? Know the properties of RTKs. Be able to describe the steps of the RTK/ras/MA pathway What is the benefit of having kinase cascades? Important Concepts Important Concepts Know the examples of ligands for the receptors Be able to describe how cellular activity is regulated by the cam pathway, starting with the binding of a ligand to the GCR, including how the g- is inactivated How are cell signaling pathways controlled What are differences and similarities between G- couple receptors, enzyme linked receptors (like RTK) and intracellular receptors Know examples of a cellular response mediated by cam 16